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  • Mitochondrial Nanotunnels
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-09-19
    Amy E. Vincent, Doug M. Turnbull, Veronica Eisner, György Hajnóczky, Martin Picard

    Insight into the regulation of complex physiological systems emerges from understanding how biological units communicate with each other. Recent findings show that mitochondria communicate at a distance with each other via nanotunnels, thin double-membrane protrusions that connect the matrices of non-adjacent mitochondria. Emerging evidence suggest that mitochondrial nanotunnels are generated by immobilized mitochondria and transport proteins. This review integrates data from the evolutionarily conserved structure and function of intercellular projections in bacteria with recent developments in mitochondrial imaging that permit nanotunnel visualization in eukaryotes. Cell type-specificity, timescales, and the selective size-based diffusion of biomolecules along nanotunnels are also discussed. The joining of individual mitochondria into dynamic networks of communicating organelles via nanotunnels and other mechanisms has major implications for organelle and cellular behaviors.

  • Phosphatidic Acid and Cardiolipin Coordinate Mitochondrial Dynamics
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-09-11
    Shoichiro Kameoka, Yoshihiro Adachi, Koji Okamoto, Miho Iijima, Hiromi Sesaki

    Membrane organelles comprise both proteins and lipids. Remodeling of these membrane structures is controlled by interactions between specific proteins and lipids. Mitochondrial structure and function depend on regulated fusion and the division of both the outer and inner membranes. Here we discuss recent advances in the regulation of mitochondrial dynamics by two critical phospholipids, phosphatidic acid (PA) and cardiolipin (CL). These two lipids interact with the core components of mitochondrial fusion and division (Opa1, mitofusin, and Drp1) to activate and inhibit these dynamin-related GTPases. Moreover, lipid-modifying enzymes such as phospholipases and lipid phosphatases may organize local lipid composition to spatially and temporarily coordinate a balance between fusion and division to establish mitochondrial morphology.

  • Rebuilding Chromosomes After Catastrophe: Emerging Mechanisms of Chromothripsis
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-09-09
    Peter Ly, Don W. Cleveland

    Cancer genome sequencing has identified chromothripsis, a complex class of structural genomic rearrangements involving the apparent shattering of an individual chromosome into tens to hundreds of fragments. An initial error during mitosis, producing either chromosome mis-segregation into a micronucleus or chromatin bridge interconnecting two daughter cells, can trigger the catastrophic pulverization of the spatially isolated chromosome. The resultant chromosomal fragments are religated in random order by DNA double-strand break repair during the subsequent interphase. Chromothripsis scars the cancer genome with localized DNA rearrangements that frequently generate extensive copy number alterations, oncogenic gene fusion products, and/or tumor suppressor gene inactivation. Here we review emerging mechanisms underlying chromothripsis with a focus on the contribution of cell division errors caused by centromere dysfunction.

  • Nuclear Lamins: Thin Filaments with Major Functions
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-09-08
    Rebecca de Leeuw, Yosef Gruenbaum, Ohad Medalia

    The nuclear lamina is a nuclear peripheral meshwork that is mainly composed of nuclear lamins, although a small fraction of lamins also localizes throughout the nucleoplasm. Lamins are classified as type V intermediate filament (IF) proteins. Mutations in lamin genes cause at least 15 distinct human diseases, collectively termed laminopathies, including muscle, metabolic, and neuronal diseases, and can cause accelerated aging. Most of these mutations are in the LMNA gene encoding A-type lamins. A growing number of nuclear proteins are known to bind lamins and are implicated in both nuclear and cytoskeletal organization, mechanical stability, chromatin organization, signaling, gene regulation, genome stability, and cell differentiation. Recent studies reveal the organization of the lamin filament meshwork in somatic cells where they assemble as tetramers in cross-section of the filaments.

  • Rethinking HSF1 in Stress, Development, and Organismal Health
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-09-07
    Jian Li, Johnathan Labbadia, Richard I. Morimoto

    The heat shock response (HSR) was originally discovered as a transcriptional response to elevated temperature shock and led to the identification of heat shock proteins and heat shock factor 1 (HSF1). Since then HSF1 has been shown to be important for combating other forms of environmental perturbations as well as genetic variations that cause proteotoxic stress. The HSR has long been thought to be an absolute response to conditions of cell stress and the primary mechanism by which HSF1 promotes organismal health by preventing protein aggregation and subsequent proteome imbalance. Accumulating evidence now shows that HSF1, the central player in the HSR, is regulated according to specific cellular requirements through cell-autonomous and non-autonomous signals, and directs transcriptional programs distinct from the HSR during development and in carcinogenesis. We discuss here these ‘non-canonical’ roles of HSF1, its regulation in diverse conditions of development, reproduction, metabolism, and aging, and posit that HSF1 serves to integrate diverse biological and pathological responses.

  • The Ire1 Twist that Links Proteostatic with Lipostatic Control of the Endoplasmic Reticulum
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-09-05
    Tomás Aragón, Eelco van Anken

    The unfolded protein response (UPR) governs homeostasis of both luminal content and membrane of the endoplasmic reticulum (ER). In Molecular Cell, Halbleib et al. identified how a twist in the juxta-membrane amphipathic helix of the UPR transducer Ire1 in yeast is essential for responding to both proteostatic and lipostatic ER stress.

  • Proinflammatory Signals as Fuel for the Fire of Hematopoietic Stem Cell Emergence
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-09-04
    Raquel Espin-Palazon, Bart Weijts, Victor Mulero, David Traver

    Hematopoietic stem cells (HSCs) have the extraordinary ability to both self-renew and generate all mature blood cell lineages. The ability to produce or expand patient-derived HSCs in vitro would greatly improve the outcome for patients with blood disorders that are currently treated with allogeneic HSC transplantation. Many laboratories have been working to identify the signals required for HSC emergence in their native environments to apply this knowledge in vitro. Recently, several signals traditionally known to underlie classical inflammation have emerged as essential regulators of HSC development. In this review we synthesize the findings that have established inflammatory cues as key regulators of HSC development.

  • cGAS Conducts Micronuclei DNA Surveillance
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-09-04
    Carina C. de Oliveira Mann, Philip J. Kranzusch

    DNA damage elicits a potent proinflammatory immune response. A collection of four papers now reveals that micronuclear DNA is a new cell intrinsic immunostimulatory molecule, and that accumulation of the immune sensor cyclic GMP–AMP synthase (cGAS) in micronuclei leads to a cell-cycle-dependent proinflammatory response following DNA damage.

  • Acylglycerol Kinase: Mitochondrial Protein Transport Meets Lipid Biosynthesis
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-08-31
    Christoph U. Mårtensson, Thomas Becker

    The carrier translocase (TIM22 complex) inserts hydrophobic proteins into the mitochondrial inner membrane. Recently, the acylglycerol kinase (AGK) mutated in Sengers syndrome was identified as a novel subunit of the human TIM22 complex. This finding reveals an exciting link between mitochondrial protein and lipid biogenesis.

  • Emerging Roles for the Lysosome in Lipid Metabolism
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-08-30
    Ashley M. Thelen, Roberto Zoncu

    Precise regulation of lipid biosynthesis, transport, and storage is key to the homeostasis of cells and organisms. Cells rely on a sophisticated but poorly understood network of vesicular and nonvesicular transport mechanisms to ensure efficient delivery of lipids to target organelles. The lysosome stands at the crossroads of this network due to its ability to process and sort exogenous and endogenous lipids. The lipid-sorting function of the lysosome is intimately connected to its recently discovered role as a metabolic command-and-control center, which relays multiple nutrient cues to the master growth regulator, mechanistic target of rapamycin complex (mTORC)1 kinase. In turn, mTORC1 potently drives anabolic processes, including de novo lipid synthesis, while inhibiting lipid catabolism. Here, we describe the dual role of the lysosome in lipid transport and biogenesis, and we discuss how integration of these two processes may play important roles both in normal physiology and in disease.

  • Ki-67 and the Chromosome Periphery Compartment in Mitosis
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-08-23
    Daniel G. Booth, William C. Earnshaw

    The chromosome periphery is a complex network of proteins and RNA molecules (many derived from nucleoli) that covers the outer surface of chromosomes and whose function remains mysterious. Although it was first described over 130 years ago, technological advances and the recent discovery that Ki-67 acts as an organiser of this region have allowed the chromosome periphery to be dissected in previously unattainable detail, leading to a revival of interest in this obscure chromosomal compartment. Here, we review the most recent advances into the composition, structure and function of the chromosome periphery, discuss possible roles of Ki-67 during mitosis and consider why this structure is likely to remain the focus of ongoing attention in the future.

  • Nuclear Pore Complexes: A Scaffold Regulating Developmental Transcription?
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-07-19
    Atsushi Satomura, Jason H. Brickner

    Nuclear pore complexes (NPCs) have a conserved, but poorly understood, role in transcriptional regulation. Recently, in Developmental Cell, Raices et al. argued that tissue-specific nuclear pore proteins (Nups) act as scaffolds that recruit the transcription factor Mef2C to the NPC, promoting transcription of NPC-associated genes during muscle development.

  • Using Force to Punch Holes: Mechanics of Contractile Nanomachines
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-06-12
    Maximilian Brackmann, Sergey Nazarov, Jing Wang, Marek Basler

    Using physical force to translocate macromolecules across a membrane has the advantage of being a universal solution independent of the properties of the target membrane. However, physically punching a stiff membrane is not a trivial task and three things are necessary for success: a sharp tip, a source of energy, and the ability to strongly bind to the target. In this review we describe the basic mechanism of membrane puncturing by contractile nanomachines with a focus on the T4 phage, R-type pyocin, and the bacterial Type VI secretion system (T6SS) based on recent studies of the structures and dynamics of their assembly.

  • Functional Properties of the Mitochondrial Carrier System
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-05-15
    Eric B. Taylor

    The mitochondrial carrier system (MCS) transports small molecules between mitochondria and the cytoplasm. It is integral to the core mitochondrial function to regulate cellular chemistry by metabolism. The mammalian MCS comprises the transporters of the 53-member canonical SLC25A family and a lesser number of identified noncanonical transporters. The recent discovery and investigations of the mitochondrial pyruvate carrier (MPC) illustrate the diverse effects a single mitochondrial carrier may exert on cellular function. However, the transport selectivities of many carriers remain unknown, and most have not been functionally investigated in mammalian cells. The mechanisms coordinating their function as a unified system remain undefined. Increased accessibility to molecular genetic and metabolomic technologies now greatly enables investigation of the MCS. Continued investigation of the MCS may reveal how mitochondria encode complex regulatory information within chemical thermodynamic gradients. This understanding may enable precision modulation of cellular chemistry to counteract the dysmetabolism inherent in disease.

  • Serine and Functional Metabolites in Cancer
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-06-07
    Alice C. Newman, Oliver D.K. Maddocks

    Folate metabolism functions to supply one-carbon units that are vital for a range of biochemical reactions. Cancer cells can utilise serine as a major source of one-carbon units, rendering them dependent upon extracellular serine uptake or de novo serine synthesis for maximal growth and proliferation. One-carbon units are required for the production of critical cellular components, such as nucleotides, which enable cancer cells to maintain high proliferate rates. Of recent interest, one-carbon metabolism contributes to the biosynthesis and recycling of functional metabolites, such as ATP, S-adenosyl-methionine (SAM), and NAD(P)H, with important downstream consequences for cancer cell survival. In this review, we describe recent advances in our understanding of the importance of one-carbon metabolism in cancer, focussing upon the routes through which cancer cells obtain and use one-carbon units.

  • Transforming Growth Factor-β Receptors and Smads: Regulatory Complexity and Functional Versatility
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-05-25
    Erine H. Budi, Dana Duan, Rik Derynck

    Transforming growth factor (TGF)-β family proteins control cell physiology, proliferation, and growth, and direct cell differentiation, thus playing key roles in normal development and disease. The mechanisms of how TGF-β family ligands interact with heteromeric complexes of cell surface receptors to then activate Smad signaling that directs changes in gene expression are often seen as established. Even though TGF-β-induced Smad signaling may be seen as a linear signaling pathway with predictable outcomes, this pathway provides cells with a versatile means to induce different cellular responses. Fundamental questions remain as to how, at the molecular level, TGF-β and TGF-β family proteins activate the receptor complexes and induce a context-dependent diversity of cell responses. Among the areas of progress, we summarize new insights into how cells control TGF-β responsiveness by controlling the TGF-β receptors, and into the key roles and versatility of Smads in directing cell differentiation and cell fate selection.

  • Gasdermins: Effectors of Pyroptosis
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-06-12
    Stephen B. Kovacs, Edward A. Miao

    Pyroptosis is a form of lytic programmed cell death initiated by inflammasomes, which detect cytosolic contamination or perturbation. This drives activation of caspase-1 or caspase-11/4/5, which cleave gasdermin D, separating its N-terminal pore-forming domain (PFD) from the C-terminal repressor domain (RD). The PFD oligomerizes to form large pores in the membrane that drive swelling and membrane rupture. Gasdermin D is one of six (in humans) gasdermin family members; several other gasdermins have also been shown to form pores that cause pyroptosis after cleavage to activate their PFDs. One of these, gasdermin E, is activated by caspase-3 cleavage. We review our current understanding of pyroptosis as well as current knowledge of the gasdermin family.

  • Mining for Micropeptides
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-05-18
    Catherine A. Makarewich, Eric N. Olson

    Advances in computational biology and large-scale transcriptome analyses have revealed that a much larger portion of the genome is transcribed than was previously recognized, resulting in the production of a diverse population of RNA molecules with both protein-coding and noncoding potential. Emerging evidence indicates that several RNA molecules have been mis-annotated as noncoding and in fact harbor short open reading frames (sORFs) that encode functional peptides and that have evaded detection until now due to their small size. sORF-encoded peptides (SEPs), or micropeptides, have been shown to have important roles in fundamental biological processes and in the maintenance of cellular homeostasis. These small proteins can act independently, for example as ligands or signaling molecules, or they can exert their biological functions by engaging with and modulating larger regulatory proteins. Given their small size, micropeptides may be uniquely suited to fine-tune complex biological systems.

  • Spatial and Temporal Control of Senescence
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-08-17
    Yoko Ito, Matthew Hoare, Masashi Narita

    Cellular senescence is an autonomous tumor suppressor mechanism leading to stable cell cycle arrest. Senescent cells are highly secretory, driving a range of different functions through the senescence-associated secretory phenotype (SASP). Recent findings have suggested that the composition of the SASP is dynamically and spatially regulated and that the changing composition of the SASP can determine the beneficial and detrimental aspects of the senescence program, tipping the balance to either an immunosuppressive/profibrotic environment or proinflammatory/fibrolytic state. Here, we discuss the current understanding of the temporal and spatial regulation of the SASP and the novel finding of NOTCH signaling as a regulator of SASP composition.

  • Lymphocyte Fate and Metabolism: A Clonal Balancing Act
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-08-14
    Simone A. Nish, Wen-Hsuan W. Lin, Steven L. Reiner

    Activated lymphocytes perform a clonal balancing act, yielding a daughter cell that differentiates owing to intense PI3K signaling, alongside a self-renewing sibling cell with blunted anabolic signaling. Divergent cellular anabolism versus catabolism is emerging as a feature of several developmental and regenerative paradigms. Metabolism can dictate cell fate, in part, because lineage-specific regulators are embedded in the circuitry of conserved metabolic switches. Unequal transmission of PI3K signaling during regenerative divisions is reminiscent of compartmentalized PI3K activity during directed motility or polarized information flow in non-dividing cells. The diverse roles of PI3K pathways in membrane traffic, cell polarity, metabolism, and gene expression may have converged to instruct sibling cell feast and famine, thereby enabling clonal differentiation alongside self-renewal.

  • Interface between Physics and Biology: Training a New Generation of Creative Bilingual Scientists
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-06-22
    Daniel Riveline, Karsten Kruse

    Whereas physics seeks for universal laws underlying natural phenomena, biology accounts for complexity and specificity of molecular details. Contemporary biological physics requires people capable of working at this interface. New programs prepare scientists who transform respective disciplinary views into innovative approaches for solving outstanding problems in the life sciences.

  • TREX1 Cuts Down on Cancer Immunogenicity
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-06-15
    Takahiro Yamazaki, Lorenzo Galluzzi

    Demaria and colleagues have recently identified three prime repair exonuclease 1 (TREX1) as a key determinant for the limited immunogenicity of cancer cells responding to single high-dose radiation. TREX1 stands out as a promising target for the development of novel strategies to boost anticancer immune responses driven by radiation therapy (RT).

  • Bursting the Bubble – Nuclear Envelope Rupture as a Path to Genomic Instability?
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-03-09
    Pragya Shah, Katarina Wolf, Jan Lammerding

    The nuclear envelope safeguards the genetic material inside the nucleus by separating it from the cytoplasm. Until recently, it was assumed that nuclear envelope (NE) breakdown occurs only in a highly controlled fashion during mitosis when the chromatin is condensed and divided between the daughter cells. However, recent studies have demonstrated that adherent and migrating cells exhibit transient NE rupture during interphase caused by compression from cytoskeletal or external forces. NE rupture results in uncontrolled exchange between the nuclear interior and cytoplasm and leads to DNA damage. In this review, we discuss the causes and consequences of NE rupture, and how NE rupture could contribute to genomic instability.

  • Mammary Stem Cells: Premise, Properties, and Perspectives
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-05-06
    Bethan Lloyd-Lewis, Olivia B. Harris, Christine J. Watson, Felicity M. Davis

    Adult mammary stem cells (MaSCs) drive postnatal organogenesis and remodeling in the mammary gland, and their longevity and potential have important implications for breast cancer. However, despite intense investigation the identity, location, and differentiation potential of MaSCs remain subject to deliberation. The application of genetic lineage-tracing models, combined with quantitative 3D imaging and biophysical methods, has provided new insights into the mammary epithelial hierarchy that challenge classical definitions of MaSC potency and behaviors. We review here recent advances – discussing fundamental unresolved properties of MaSC potency, dynamics, and plasticity – and point to evolving technologies that promise to shed new light on this intractable debate. Elucidation of the physiological mammary differentiation hierarchy is paramount to understanding the complex heterogeneous breast cancer landscape.

  • Ubiquitin-Dependent Regulation of Stem Cell Biology
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-05-18
    Achim Werner, Andrew G. Manford, Michael Rape

    The growth of a metazoan body relies on a series of highly coordinated cell-fate decisions by stem cells which can undergo self-renewal, reversibly enter a quiescent state, or terminally commit to a cell specification program. To guide their decisions, stem cells make frequent use of ubiquitylation, a post-translational modification that can affect the activity, interaction landscape, or stability of stem cell proteins. In this review we discuss novel findings that have provided insight into ubiquitin-dependent mechanisms of stem cell control and revealed how an essential and highly conserved protein modification can shape metazoan development.

  • Stop or Go? Endosome Positioning in the Establishment of Compartment Architecture, Dynamics, and Function
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-03-28
    Jacques Neefjes, Marlieke M.L. Jongsma, Ilana Berlin

    The endosomal system constitutes a key negotiator between the environment of a cell and its internal affairs. Comprised of a complex membranous network, wherein each vesicle can in principle move autonomously throughout the cell, the endosomal system operates as a coherent unit to optimally face external challenges and maintain homeostasis. Our appreciation of how individual endosomes are controlled in time and space to best serve their collective purpose has evolved dramatically in recent years. In light of these efforts, the endoplasmic reticulum (ER) – with its expanse of membranes permeating the cytoplasmic space – has emerged as a potent spatiotemporal organizer of endosome biology. We review the latest advances in our understanding of the mechanisms underpinning endosomal transport and positioning, with emphasis on the contributions from the ER, and offer a perspective on how the interplay between these aspects shapes the architecture and dynamics of the endosomal system and drives its myriad cellular functions.

  • Tumor Cell Invadopodia: Invasive Protrusions that Orchestrate Metastasis
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-04-12
    Robert J. Eddy, Maxwell D. Weidmann, Ved P. Sharma, John S. Condeelis

    Invadopodia are a subset of invadosomes that are implicated in the integration of signals from the tumor microenvironment to support tumor cell invasion and dissemination. Recent progress has begun to define how tumor cells regulate the plasticity necessary for invadopodia to assemble and function efficiently in the different microenvironments encountered during dissemination in vivo. Exquisite mapping by many laboratories of the pathways involved in integrating diverse invadopodium initiation signals, from growth factors, to extracellular matrix (ECM) and cell–cell contact in the tumor microenvironment, has led to insight into the molecular basis of this plasticity. Here, we integrate this new information to discuss how the invadopodium is an important conductor that orchestrates tumor cell dissemination during metastasis.

  • rAMPing Up Stress Signaling: Protein AMPylation in Metazoans
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-04-19
    Matthias C. Truttmann, Hidde L. Ploegh

    Protein AMPylation – the covalent attachment of an AMP residue to amino acid side chains using ATP as the donor – is a post-translational modification (PTM) increasingly appreciated as relevant for both normal and pathological cell signaling. In metazoans single copies of filamentation induced by cAMP (fic)-domain-containing AMPylases – the enzymes responsible for AMPylation – preferentially modify a set of dedicated targets and contribute to the perception of cellular stress and its regulation. Pathogenic bacteria can exploit AMPylation of eukaryotic target proteins to rewire host cell signaling machinery in support of their propagation and survival. We review endogenous as well as parasitic protein AMPylation in metazoans and summarize current views of how fic-domain-containing AMPylases contribute to cellular proteostasis.

  • The Mediator Complex: At the Nexus of RNA Polymerase II Transcription
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-08-01
    Célia Jeronimo, François Robert

    Mediator is an essential, large, multisubunit, transcriptional co-activator highly conserved across eukaryotes. Mediator interacts with gene-specific transcription factors at enhancers as well as with the RNA polymerase II (RNAPII) transcription machinery bound at promoters. It also interacts with several other factors involved in various aspects of transcription, chromatin regulation, and mRNA processing. Hence, Mediator is at the nexus of RNAPII transcription, regulating its many steps and connecting transcription with co-transcriptional events. To achieve this flexible role, Mediator, which is divided into several functional modules, reorganizes its conformation and composition while making transient contacts with other components. Here, we review the mechanisms of action of Mediator and propose a unifying model for its function.

  • Neural Glycosylphosphatidylinositol-Anchored Proteins in Synaptic Specification
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-07-22
    Ji Won Um, Jaewon Ko

    Glycosylphosphatidylinositol (GPI)-anchored proteins are a specialized class of lipid-associated neuronal membrane proteins that perform diverse functions in the dynamic control of axon guidance, synaptic adhesion, cytoskeletal remodeling, and localized signal transduction, particularly at lipid raft domains. Recent studies have demonstrated that a subset of GPI-anchored proteins act as critical regulators of synapse development by modulating specific synaptic adhesion pathways via direct interactions with key synapse-organizing proteins. Additional studies have revealed that alteration of these regulatory mechanisms may underlie various brain disorders. In this review, we highlight the emerging role of GPI-anchored proteins as key synapse organizers that aid in shaping the properties of various types of synapses and circuits in mammals.

  • Metabolic Interactions in the Tumor Microenvironment
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-07-19
    Costas A. Lyssiotis, Alec C. Kimmelman

    Tumors are dynamic pseudoorgans that contain numerous cell types interacting to create a unique physiology. Within this network, the malignant cells encounter many challenges and rewire their metabolic properties accordingly. Such changes can be experienced and executed autonomously or through interaction with other cells in the tumor. The focus of this review is on the remodeling of the tumor microenvironment that leads to pathophysiologic interactions that are influenced and shaped by metabolism. They include symbiotic nutrient sharing, nutrient competition, and the role of metabolites as signaling molecules. Examples of such processes abound in normal organismal physiology, and such heterocellular metabolic interactions are repurposed to support tumor metabolism and growth. The importance and ubiquity of these processes are just beginning to be realized, and insights into their role in tumor development and progression are being used to design new drug targets and cancer therapies.

  • Hierarchy and Plasticity in the Intestinal Stem Cell Compartment
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-07-18
    Maryam Yousefi, Linheng Li, Christopher J. Lengner

    Somatic stem cells maintain tissue homeostasis by organizing themselves in such a way that they can maintain proliferative output while simultaneously protecting themselves from DNA damage that may lead to oncogenic transformation. There is considerable debate about how such stem cell compartments are organized. Burgeoning evidence from the small intestine and colon provides support for a two-stem cell model involving an actively proliferating but injury-sensitive stem cell and a rare, injury-resistant pool of quiescent stem cells. Parallel with this evidence, recent studies have revealed considerable plasticity within the intestinal stem cell (ISC) compartment. We discuss the evidence for plasticity and hierarchy within the ISC compartment and how these properties govern tissue regeneration and contribute to oncogenic transformation leading to colorectal cancers.

  • Chromosome Intermingling: Mechanical Hotspots for Genome Regulation
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-07-17
    Caroline Uhler, G.V. Shivashankar

    Cells sense physical and chemical signals from their local microenvironment and transduce them to the nucleus to regulate genomic programs. In this review, we first discuss different modes of mechanotransduction to the nucleus. We then highlight the role of the spatial organization of chromosomes for integrating these signals. In particular, we emphasize the importance of chromosome intermingling for gene regulation. We also discuss various geometric models and recent advances in microscopy and genomics that have allowed access to these nanoscale chromosome intermingling regions. Taken together, the recent work summarized in this review culminates in the hypothesis that chromosome intermingling regions are mechanical hotspots for genome regulation. Maintenance of such mechanical hotspots is crucial for cellular homeostasis, and alterations in them could be precursors for various cellular reprogramming events, including diseases.

  • Oncogenic Activities of IDH1/2 Mutations: From Epigenetics to Cellular Signaling
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-07-12
    Laurence M. Gagné, Karine Boulay, Ivan Topisirovic, Marc-Étienne Huot, Frédérick A. Mallette

    Gliomas and leukemias remain highly refractory to treatment, thus highlighting the need for new and improved therapeutic strategies. Mutations in genes encoding enzymes involved in the tricarboxylic acid (TCA) cycle, such as the isocitrate dehydrogenases 1 and 2 (IDH1/2), are frequently encountered in astrocytomas and secondary glioblastomas, as well as in acute myeloid leukemias; however, the precise molecular mechanisms by which these mutations promote tumorigenesis remain to be fully characterized. Gain-of-function mutations in IDH1/2 have been shown to stimulate production of the oncogenic metabolite R-2-hydroxyglutarate (R-2HG), which inhibits α-ketoglutarate (αKG)-dependent enzymes. We review recent advances on the elucidation of oncogenic functions of IDH1/2 mutations, and of the associated oncometabolite R-2HG, which link altered metabolism of cancer cells to epigenetics, RNA methylation, cellular signaling, hypoxic response, and DNA repair.

  • Tensins: Bridging AMP-Activated Protein Kinase with Integrin Activation
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-07-08
    Maria Georgiadou, Johanna Ivaska

    Integrin activation is essential for cell adhesion and for connecting the extracellular matrix to the actin cytoskeleton. Thus, inappropriate integrin activation has been linked to several diseases, including cancer. Recent insights demonstrate that the main fibrillar adhesion component tensin maintains β1-integrin active in these mature adhesions. Depletion or silencing of AMP-activated protein kinase (AMPK), the energy sensor involved in maintaining the energy balance of the cell, enhances integrin activity by increasing the expression of tensin and thereby promoting cell adhesion, matrix formation, and mechanotransduction. Here, we discuss the role of tensin and AMPK in the regulation of integrin activity and integrin-dependent processes and their implication in diseases such as cancer and tissue fibrosis.

  • Disentangling a Bad Reputation: Changing Perceptions of Amyloids
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-03-27
    Miling Wang, Timothy E. Audas, Stephen Lee

    Historically, amyloids were perceived as toxic/irreversible protein aggregates associated with neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. Recent papers are challenging this perception by uncovering widespread cellular roles for physiological amyloidogenesis. These findings suggest that the amyloid-fold should be considered, alongside the native-fold and unfolded configurations, as a physiological and reversible protein organization.

  • α-Synuclein – Regulator of Exocytosis, Endocytosis, or Both?
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-03-02
    Janin Lautenschläger, Clemens F. Kaminski, Gabriele S. Kaminski Schierle

    α-Synuclein is known as a presynaptic protein that binds to small synaptic vesicles. Recent studies suggest that α-synuclein is not only attracted to these tiny and therewith highly curved membranes, but that in fact the sensing and regulation of membrane curvature is part of its physiological function. Moreover, recent studies have suggested that α-synuclein plays a role in the endocytosis of synaptic vesicles, and have provided support for a function of α-synuclein during exo- and endocytosis in which curvature sensing and membrane stabilization are crucial steps. This review aims to highlight recent research in the field and adds a new picture on the function of α-synuclein in maintaining synaptic homeostasis upon intense and repetitive neuronal activity.

  • ALUternative Regulation for Gene Expression
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-02-10
    Ling-Ling Chen, Li Yang

    Alu elements belong to the primate-specific SINE family of retrotransposons and constitute almost 11% of the human genome. Alus are transcribed by RNA polymerase (Pol) III and are inserted back into the genome with the help of autonomous LINE retroelements. Since Alu elements are preferentially located near to or within gene-rich regions, they can affect gene expression by distinct mechanisms of action at both DNA and RNA levels. In this review we focus on recent advances of how Alu elements are pervasively involved in gene regulation. We discuss the impacts of Alu DNA sequences that are in close proximity to genes, Pol-III-transcribed free Alu RNAs, and Pol-II-transcribed Alu RNAs that are embedded within coding or noncoding RNA transcripts. The recent elucidation of Alu functions reveals previously underestimated roles of these selfish or junk DNA sequences in the human genome.

  • Autophagy Receptors and Neurodegenerative Diseases
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-02-03
    Zhiqiang Deng, Kerry Purtell, Veronik Lachance, Mitchell S. Wold, Shi Chen, Zhenyu Yue

    Previously thought of as a nonselective digestion process, autophagy is now known to specifically degrade aggregated proteins and damaged cellular organelles through the action of autophagy receptors, which provides cellular quality control and maintains homeostasis. Autophagy receptors recognize and recruit specific cargoes to the autophagosome–lysosome pathway for degradation in ubiquitin-dependent and -independent manners, and their functions (in selective autophagy) are regulated by protein modifications, for example, phosphorylation and ubiquitination. Growing evidence has linked the genetic variants of autophagy receptors to neurodegenerative diseases and multiple experimental systems have validated their roles in modulating the disease process. Here, we review the recent advances in understanding the physiology and pathophysiology of autophagy receptors in selective autophagy, and discuss their potentials as therapeutic targets for neurodegenerative diseases.

  • Moonlighting Motors: Kinesin, Dynein, and Cell Polarity
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-03-08
    Wen Lu, Vladimir I. Gelfand

    In addition to their well-known role in transporting cargoes in the cytoplasm, microtubule motors organize their own tracks – the microtubules. While this function is mostly studied in the context of cell division, it is essential for microtubule organization and generation of cell polarity in interphase cells. Kinesin-1, the most abundant microtubule motor, plays a role in the initial formation of neurites. This review describes the mechanism of kinesin-1-driven microtubule sliding and discusses its biological significance in neurons. Recent studies describing the interplay between kinesin-1 and cytoplasmic dynein in the translocation of microtubules are discussed. In addition, we evaluate recent work exploring the developmental regulation of microtubule sliding during axonal outgrowth and regeneration. Collectively, the discussed works suggest that sliding of interphase microtubules by motors is a novel force-generating mechanism that reorganizes the cytoskeleton and drives shape change and polarization.

  • Actin Waves: Origin of Cell Polarization and Migration?
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-03-07
    Naoyuki Inagaki, Hiroko Katsuno

    Actin filaments and associated proteins undergo wave-like movement in various cell types. Recent studies with cutting-edge analyses, including live-cell imaging, biophysical monitoring and manipulation, and mathematical modeling, have highlighted roles of ‘actin waves’ in cellular protrusion, polarization, and migration. The prevailing models to explain the wave-like dynamics of actin filaments involve an activator–inhibitor mechanism. In addition, axonal actin waves migrate by means of directional assembly and disassembly of membrane-anchored actin filaments, and thus represent a new type of machinery that translocates their component molecules to the cell edge. Here, we review recent advances in our understanding of the generation, mobility, and functions of actin waves, and discuss how actin waves may self-organize into the molecular machinery underlying cell morphogenesis.

  • Breaking Symmetry − Asymmetric Histone Inheritance in Stem Cells
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-03-06
    Jing Xie, Matthew Wooten, Vuong Tran, Xin Chen

    Asymmetric cell division (ACD) gives rise to two daughter cells with distinct fates. ACD is widely used during development and by many types of adult stem cells during tissue homeostasis and regeneration. ACD can be regulated by extrinsic cues, such as signaling molecules, as well as by intrinsic factors, such as organelles and cortex proteins. The recent discovery of asymmetric histone inheritance during stem cell ACD has revealed another intrinsic mechanism by which ACD produces two distinct daughters. In this review we discuss these findings in the context of cell-cycle regulation, as well as other studies of ACD, to begin understanding the underlying mechanisms and biological relevance of this phenomenon.

  • Novel Structural Insights into GPCR–β-Arrestin Interaction and Signaling
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-06-23
    Ravi Ranjan, Hemlata Dwivedi, Mithu Baidya, Mohit Kumar, Arun K. Shukla

    G protein-coupled receptors (GPCRs) are major signal recognition and transmission units in the plasma membrane. The interaction of activated and phosphorylated GPCRs with the multifunctional adaptor proteins β-arrestins (βarrs) is crucial for regulation of their signaling and functional outcomes. Over the past few years, a range of structural, biochemical, and cellular studies have revealed novel insights into GPCR–βarr interaction and signaling. Some of these findings have come as a surprise and therefore have the potential to significantly refine the conceptual framework of the GPCR–βarr system. Here we discuss these recent advances with particular emphasis on biphasic GPCR–βarr interaction, the formation of GPCR–G-protein–βarr supercomplexes, and receptor-specific conformational signatures in βarrs. We also underline the emerging research areas that are likely to be at the center stage of investigations in the coming years.

  • Regulating Secretory Proteostasis through the Unfolded Protein Response: From Function to Therapy
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-06-21
    Lars Plate, R. Luke Wiseman

    Imbalances in secretory proteostasis induced by genetic, environmental, or aging-related insults are pathologically associated with etiologically diverse protein misfolding diseases. To protect the secretory proteome from these insults, organisms evolved stress-responsive signaling pathways that regulate the composition and activity of biologic pathways involved in secretory proteostasis maintenance. The most prominent of these is the endoplasmic reticulum (ER) unfolded protein response (UPR), which functions to regulate ER proteostasis in response to ER stress. While the signaling mechanisms involved in UPR activation are well defined, the impact of UPR activation on secretory proteostasis is only now becoming clear. Here, we highlight recent reports defining how activation of select UPR signaling pathways influences proteostasis within the ER and downstream secretory environments. Furthermore, we describe recent evidence that highlights the therapeutic potential for targeting UPR signaling pathways to correct pathologic disruption in secretory proteostasis associated with diverse types of protein misfolding diseases.

  • Apoptosis and Necroptosis as Host Defense Strategies to Prevent Viral Infection
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-06-19
    Megan H. Orzalli, Jonathan C. Kagan

    Antiviral transcriptional responses and regulated cell death are crucial components of the host response to virus infection. However, in contrast to the signaling pathways that promote antiviral transcription, those that initiate cell death following virus infection are less understood. Several recent studies have identified pattern recognition receptors (PRRs) of the mammalian innate immune system that activate cell death pathways. These same receptors also have established roles in the induction of antiviral gene expression. In this review we discuss the mechanisms by which PRRs can serve dual roles as initiators of inflammatory gene expression and as inducers of apoptosis and necroptosis following virus infection.

  • Plasticity of Mitochondrial Translation
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-06-09
    Sven Dennerlein, Cong Wang, Peter Rehling

    Mitochondria maintained a genome during evolution to synthesize core subunits of the oxidative phosphorylation system. Expression of the mitochondrial genome requires intraorganellar replication, transcription, and translation. Membrane-associated ribosomes translate mitochondrial-encoded proteins and facilitate co-translational insertion of newly synthesized polypeptides into the inner membrane. Considering that mitochondrial-encoded proteins assemble with imported, nuclear-encoded proteins into enzyme complexes of the oxidative phosphorylation system, it is expected that expression of mitochondrial genes should adapt to the availability of their nuclear-encoded partners. Recent work shows that mitochondrial translation is influenced by the cellular environment. We discuss how mitochondrial translation is affected by the cellular environment and propose models of translational plasticity that modulate mitochondrial translation in response to the availability of imported proteins.

  • Mitochondria Bioenergetic and Cognitive Functions: The Cannabinoid Link
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-05-06
    Giacomo Mancini, Tamas L. Horvath

    Despite the well-known role of chronic mitochondrial dysfunction in the pathophysiology of the brain, the impact of acute impairment of mitochondrial activity by cannabinoids on higher brain functions is unknown. In a recent paper in Nature, Hebert-Chatelain et al. elegantly uncovered the essential role that bioenergetic processes have in the regulation of higher brain functions, such as learning and memory.

  • Mitochondrial Function and Cell Size: An Allometric Relationship
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-03-08
    Teemu P. Miettinen, Mikael Björklund

    Allometric scaling of metabolic rate results in lower total mitochondrial oxygen consumption with increasing organismal size. This is considered a universal law in biology. Here, we discuss how allometric laws impose size-dependent limits to mitochondrial activity at the cellular level. This cell-size-dependent mitochondrial metabolic activity results in nonlinear scaling of metabolism in proliferating cells, which can explain size homeostasis. The allometry in mitochondrial activity can be controlled through mitochondrial fusion and fission machinery, suggesting that mitochondrial connectivity can bypass transport limitations, the presumed biophysical basis for allometry. As physical size affects cellular functionality, cell-size-dependent metabolism becomes directly relevant for development, metabolic diseases, and aging.

  • The Interplay of Axonal Energy Homeostasis and Mitochondrial Trafficking and Anchoring
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-02-20
    Zu-Hang Sheng

    Mitochondria are key cellular power plants essential for neuronal growth, survival, function, and regeneration after injury. Given their unique morphological features, neurons face exceptional challenges in maintaining energy homeostasis at distal synapses and growth cones where energy is in high demand. Efficient regulation of mitochondrial trafficking and anchoring is critical for neurons to meet altered energy requirements. Mitochondrial dysfunction and impaired transport have been implicated in several major neurological disorders. Thus, research into energy-mediated regulation of mitochondrial recruitment and redistribution is an important emerging frontier. In this review, I discuss new insights into the mechanisms regulating mitochondrial trafficking and anchoring, and provide an updated overview of how mitochondrial motility maintains energy homeostasis in axons, thus contributing to neuronal growth, regeneration, and synaptic function.

  • Inflammation and the Metabolic Syndrome: The Tissue-Specific Functions of NF-κB
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-02-23
    Leen Catrysse, Geert van Loo

    Obesity is becoming a major health concern in Western society, and medical conditions associated with obesity are grouped in the metabolic syndrome. Overnutrition activates several proinflammatory signaling pathways, leading to a condition of chronic low-grade inflammation in several metabolic tissues affecting their proper function. Nuclear factor kappa B (NF-κB) signaling is a crucial pathway in this process and has been studied extensively in the context of obesity and the metabolic syndrome. Here we give an overview of the molecular mechanisms behind the inflammatory function of NF-κB in response to overnutrition and the effect this has on several metabolic tissues.

  • New Insights into the Physiological Role of Endoplasmic Reticulum-Associated Degradation
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-01-26
    Ling Qi, Billy Tsai, Peter Arvan

    Many human diseases are associated with mutations causing protein misfolding and aggregation in the endoplasmic reticulum (ER). ER-associated degradation (ERAD) is a principal quality-control mechanism responsible for targeting misfolded ER proteins for cytosolic degradation. However, despite years of effort, the physiological role of ERAD in vivo remains largely unknown. Several recent studies have reported intriguing phenotypes of mice deficient for ERAD function in specific cell types. These studies highlight that mammalian ERAD has been designed to perform a wide-range of cell-type-specific functions in vivo in a substrate-dependent manner.

  • With the Help of MOM: Mitochondrial Contributions to Cellular Quality Control
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-03-11
    Ralf J. Braun, Benedikt Westermann

    Mitochondria are essential organelles because they have key roles in cellular energy metabolism and many other metabolic pathways. Several quality control systems have evolved to ensure that dysfunctional mitochondria are either repaired or eliminated. The activities of these pathways are crucial for cellular health because they maintain functional mitochondria. In addition, the cytosolic ubiquitin–proteasome system (UPS) and the mitochondria-associated degradation pathway (MAD) share some of their core components, are functionally tightly interconnected, and mutually modulate their activities. Thus, the mitochondrial outer membrane (MOM) actively supports quality control systems in extramitochondrial compartments. Furthermore, mitochondrial quality surveillance systems also act on cytosolic or endoplasmic reticulum (ER) substrates and modulate immune responses. Therefore, mitochondria contribute to cellular quality control and homeostasis on several levels.

  • Mitochondria and Epigenetics – Crosstalk in Homeostasis and Stress
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-03-06
    Olli Matilainen, Pedro M. Quirós, Johan Auwerx

    Through epigenetic mechanisms cells integrate environmental stimuli to fine-tune gene expression levels. Mitochondrial function is essential to provide the intermediate metabolites necessary to generate and modify epigenetic marks in the nucleus, which in turn can regulate the expression of mitochondrial proteins. In this review we summarize the function of mitochondria in the regulation of epigenetic mechanisms as a new aspect of mitonuclear communication. We focus in particular on the most common epigenetic modifications – histone acetylation and histone and DNA methylation. We also discuss the emerging field of mitochondrial DNA (mtDNA) methylation, whose physiological role remains unknown. Finally, we describe the essential role of some histone modifications in regulating the mitochondrial unfolded protein response (UPRmt) and the mitochondrial stress-dependent lifespan extension.

  • TP53 and 53BP1 Reunited
    Trends Cell Biol. (IF 15.333) Pub Date : 2016-11-17
    Thierry Soussi, Guido Kroemer

    Identified as a TP53-binding protein, 53BP1 is a key regulator of the cellular response to double-strand breaks, a TP53-independent activity. Recent data have established a new TP53-dependent function for 53BP1 in mitotic surveillance after centrosome loss.

  • A New Mode of Mitotic Surveillance
    Trends Cell Biol. (IF 15.333) Pub Date : 2017-02-07
    Bramwell G. Lambrus, Andrew J. Holland

    Cells have evolved certain precautions to preserve their genomic content during mitosis and avoid potentially oncogenic errors. Besides the well-established DNA damage checkpoint and spindle assembly checkpoint (SAC), recent observations have identified an additional mitotic failsafe referred to as the mitotic surveillance pathway. This pathway triggers a cell cycle arrest to block the growth of potentially unfit daughter cells and is activated by both prolonged mitosis and centrosome loss. Recent genome-wide screens surprisingly revealed that 53BP1 and USP28 act upstream of p53 to mediate signaling through the mitotic surveillance pathway. Here we review advances in our understanding of this failsafe and discuss how 53BP1 and USP28 adopt noncanonical roles to function in this pathway.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.