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  • Novel roles of phosphoinositides in signaling, lipid transport, and disease
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2020-01-20
    Gerald R.V. Hammond; John E. Burke

    Phosphoinositides (PPIns) are lipid signaling molecules that act as master regulators of cellular signaling. Recent studies have revealed novel roles of PPIns in myriad cellular processes and multiple human diseases mediated by misregulation of PPIn signaling. This review will present a timely summary of recent discoveries in PPIn biology, specifically their role in regulating unexpected signaling pathways, modification of signaling outcomes downstream of integral membrane proteins, and novel roles in lipid transport. This has revealed new roles of PPIns in regulating membrane trafficking, immunity, cell polarity, and response to extracellular signals. A specific focus will be on novel opportunities to target PPIn metabolism for treatment of human diseases, including cancer, pathogen infection, developmental disorders, and immune disorders.

    更新日期:2020-01-21
  • Cyclic dinucleotides at the forefront of innate immunity
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2020-01-17
    Shivam A. Zaver; Joshua J. Woodward

    Cyclic dinucleotides (CDNs) have emerged as ubiquitous signaling molecules in all domains of life. In eukaryotes, CDN signaling systems are evolutionarily ancient and have developed to sense and respond to pathogen infection. On the other hand, dysregulation of these pathways has been implicated in the pathogenesis of autoimmune diseases. Thus, CDNs have garnered major interest over recent years for their ability to elicit potent immune responses in the eukaryotic host. Similarly, ancestral CDN-based signaling systems also appear to confer immunological protection against infection in prokaryotes. Therefore, a better understanding of the host processes regulated by CDNs will be of tremendous value in many areas of research. Here, we aim to review the latest discoveries and recent trends in CDN research with a particular focus on the molecular mechanisms by which these small molecules mediate innate immunity.

    更新日期:2020-01-17
  • Structural basis for GPCR signaling by small polar versus large lipid metabolites—discovery of non-metabolite ligands
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2020-01-14
    Michael Lückmann; Mette Trauelsen; Thomas M. Frimurer; Thue W. Schwartz

    Key metabolites act through specific G protein-coupled receptors (GPCRs) as extracellular signals of fuel availability and metabolic stress. Here, we focus on the succinate receptor SUCNR1/GPR91 and the long chain fatty acid receptor FFAR1/GPR40, for which 3D structural information is available. Like other small polar acidic metabolites, succinate is excreted from the cell by transporter proteins to bind to an extracellular, solvent-exposed pocket in SUCNR1. Non-metabolite pharmacological tool compounds are currently being designed based on the structure of the SUCNR1 binding pocket. In FFAR1, differently signaling lipid mimetics bind in two distinct membrane-exposed sites corresponding to each of the lipid bilayer leaflets. Conceivably endogenous lipid ligands gain access to these sites by way of the membrane and probably occupy both sites under physiological circumstances. Design of polar agonists for a dynamic, solvent-exposed pocket in FFAR1 underlines the possibility of structure-based approaches for development of novel tool compounds even in lipid sensing metabolite GPCRs.

    更新日期:2020-01-14
  • New perspectives on integrin-dependent adhesions
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2020-01-13
    Magdalene Michael; Maddy Parsons

    Integrins are heterodimeric transmembrane receptors that connect the extracellular matrix environment to the actin cytoskeleton via adaptor molecules through assembly of a range of adhesion structures. Recent advances in biochemical, imaging and biophysical methods have enabled a deeper understanding of integrin signalling and their associated regulatory processes. The identification of the consensus integrin-based ‘adhesomes’ within the last 5 years has defined common core components of adhesion complexes and associated partners. These approaches have also uncovered unexpected adhesion protein behaviour and molecules recruited to adhesion sites that have expanded our understanding of the molecular and physical control of integrin signalling.

    更新日期:2020-01-14
  • Dissecting intercellular signaling with mass spectrometry–based proteomics
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2020-01-09
    Jonathan J. Swietlik; Ankit Sinha; Felix Meissner
    更新日期:2020-01-11
  • Mechanistic advances in axon pathfinding
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2020-01-08
    Laura E. McCormick; Stephanie L. Gupton

    The development of a functional nervous system entails establishing connectivity between appropriate synaptic partners. During axonal pathfinding, the developing axon navigates through the extracellular environment, extending toward postsynaptic targets. In the early 1900s, Ramon y Cajal suggested that the growth cone, a specialized, dynamic, and cytoskeletal-rich structure at the tip of the extending axon, is guided by chemical cues in the extracellular environment. A century of work supports this hypothesis and introduced myriad guidance cues and receptors that promote a variety of growth cone behaviors including extension, pause, collapse, retraction, turning, and branching. Here, we highlight research from the last two years regarding pathways implicated in axon pathfinding.

    更新日期:2020-01-09
  • The ATG conjugation systems in autophagy
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-12-31
    Noboru Mizushima

    Autophagosome formation and maturation involve the two ubiquitin-like systems: The ATG8 and ATG12 systems. ATG8 (LC3s and gamma-aminobutyric acid receptor–associated proteins in mammals) and ATG12 are covalently conjugated to phosphatidylethanolamine and ATG5, respectively. Although the ATG12 and ATG8 systems were discovered more than 20 years ago, their molecular functions are not fully understood. The aim of this review is to summarize recent findings related to ATG conjugation systems, focusing on current controversies regarding the genetic hierarchy of these systems, interpretation of conjugation-independent alternative macroautophagy, the differences in roles between LC3s and gamma-aminobutyric acid receptor–associated proteins in autophagosome formation and cargo recognition, and evolution of these systems.

    更新日期:2019-12-31
  • Tissue polarity and PCP protein function: C. elegans as an emerging model
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-12-26
    Janine Cravo; Sander van den Heuvel

    Polarity is the basis for the generation of cell diversity, as well as the organization, morphogenesis, and functioning of tissues. Studies in Caenorhabditis elegans have provided much insight into PAR-protein mediated polarity; however, the molecules and mechanisms critical for cell polarization within the plane of epithelia have been identified in other systems. Tissue polarity in C. elegans is organized by Wnt-signaling with some resemblance to the Wnt/planar cell polarity (PCP) pathway, but lacking core PCP protein functions. Nonetheless, recent studies revealed that conserved PCP proteins regulate directed cell migratory events in C. elegans, such as convergent extension movements and neurite formation and guidance. Here, we discuss the latest insights and use of C. elegans as a PCP model.

    更新日期:2019-12-27
  • External signal–mediated polarized growth in fungi
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-12-23
    Martine Bassilana; Charles Puerner; Robert A. Arkowitz

    As the majority of fungi are nonmotile, polarized growth in response to an external signal enables them to search for nutrients and mating partners, and hence is crucial for survival and proliferation. Although the mechanisms underlying polarization in response to external signals has commonalities with polarization during mitotic division, during budding, and fission growth, the importance of diverse feedback loops regulating external signal–mediated polarized growth is likely to be distinct and uniquely adapted to a dynamic environment. Here, we highlight recent advances in our understanding of the mechanisms that are crucial for polarity in response to external signals in fungi, with particular focus on the roles of membrane traffic, small GTPases, and lipids, as well as the interplay between cell shape and cell growth.

    更新日期:2019-12-25
  • Building an apical domain in the early mouse embryo: Lessons, challenges and perspectives
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-12-21
    Meng Zhu; Magdalena Zernicka-Goetz

    Cell polarization is critical for lineage segregation and morphogenesis during mammalian embryogenesis. However, the processes and mechanisms that establish cell polarity in the mammalian embryo are not well understood. Recent studies suggest that unique regulatory mechanisms are deployed by the mouse embryo to establish cell polarization. In this review, we discuss the current understanding of cell polarity establishment, focusing on the formation of the apical domain in the mouse embryo. We will also discuss outstanding questions and possible directions for future study.

    更新日期:2019-12-21
  • Emerging roles for the nucleus during neutrophil signal relay and NETosis
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-12-10
    Cosmo A. Saunders, Carole A. Parent

    The nucleus houses and protects genomic DNA, which is surrounded by the nuclear envelope. Owing to its size and stiffness, the nucleus is often a barrier to migration through confined spaces. Neutrophils are terminally differentiated, short-lived cells that migrate through tissues in response to injury and infections. The neutrophil nucleus is soft, multilobular, and exhibits altered levels of key nuclear envelope proteins. These alterations result in a multifunctional organelle that serves as a signaling hub during migration and NETosis, a process by which neutrophils release decondensed chromatin decorated with granular enzymes that entrap pathogens. In this review, we present emerging evidence suggesting that a unique, ambiguous cell-cycle state is critical for NETosis and migration. Finally, we discuss how the mechanisms underlying migration and NETosis are evolutionarily conserved.

    更新日期:2019-12-11
  • Patterning and polarization of cells by intracellular flows
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-11-21
    Rukshala Illukkumbura, Tom Bland, Nathan W. Goehring

    Beginning with Turing's seminal work [1], decades of research have demonstrated the fundamental ability of biochemical networks to generate and sustain the formation of patterns. However, it is increasingly appreciated that biochemical networks also both shape and are shaped by physical and mechanical processes [2, 3, 4]. One such process is fluid flow. In many respects, the cytoplasm, membrane and actin cortex all function as fluids, and as they flow, they drive bulk transport of molecules throughout the cell. By coupling biochemical activity to long-range molecular transport, flows can shape the distributions of molecules in space. Here, we review the various types of flows that exist in cells, with the aim of highlighting recent advances in our understanding of how flows are generated and how they contribute to intracellular patterning processes, such as the establishment of cell polarity.

    更新日期:2019-11-22
  • The Golgi apparatus and cell polarity: Roles of the cytoskeleton, the Golgi matrix, and Golgi membranes
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-11-18
    Yamini Ravichandran, Bruno Goud, Jean-Baptiste Manneville

    Membrane trafficking plays a crucial role in cell polarity by directing lipids and proteins to specific subcellular locations in the cell and sustaining a polarized state. The Golgi apparatus, the master organizer of membrane trafficking, can be subdivided into three layers that play different mechanical roles: a cytoskeletal layer, the so-called Golgi matrix, and the Golgi membranes. First, the outer regions of the Golgi apparatus interact with cytoskeletal elements, mainly actin and microtubules, which shape, position, and orient the organelle. Closer to the Golgi membranes, a matrix of long coiled–coiled proteins not only selectively captures transport intermediates but also participates in signaling events during polarization of membrane trafficking. Finally, the Golgi membranes themselves serve as active signaling platforms during cell polarity events. We review here the recent findings that link the Golgi apparatus to cell polarity, focusing on the roles of the cytoskeleton, the Golgi matrix, and the Golgi membranes.

    更新日期:2019-11-19
  • Multicellular scale front-to-rear polarity in collective migration
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-11-19
    Lavinia Capuana, Astrid Boström, Sandrine Etienne-Manneville

    Collective cell migration does not only reflect the migration of cells at a similar speed and in the same direction, it also implies the emergence of new properties observed at the level of the cell group. This collective behavior relies on interactions between the cells and the establishment of a hierarchy amongst cells with leaders driving the group of followers. Here, we make the parallel between the front-to-rear polarity axis in single cell and the front-to-rear multicellular-scale polarity of a migrating collective which established through exchange of biochemical and mechanical information from the front to the rear and vice versa. Such multicellular-scale polarity gives the migrating group the possibility to better sense and adapt to energy, biochemical and mechanical constraints and facilitates migration over long distances in complex and changing environments.

    更新日期:2019-11-19
  • Generation and regulation of microtubule network asymmetry to drive cell polarity
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-11-15
    Joyce C.M. Meiring, Boris I. Shneyer, Anna Akhmanova

    Microtubules control cell architecture by serving as a scaffold for intracellular transport, signaling, and organelle positioning. Microtubules are intrinsically polarized, and their orientation, density, and post-translational modifications both respond and contribute to cell polarity. Animal cells that can rapidly reorient their polarity axis, such as fibroblasts, immune cells, and cancer cells, contain radially organized microtubule arrays anchored at the centrosome and the Golgi apparatus, whereas stably polarized cells often acquire non-centrosomal microtubule networks attached to the cell cortex, nucleus, or other structures. Microtubule density, longevity, and post-translational modifications strongly depend on the dynamics of their plus ends. Factors controlling microtubule plus-end dynamics are often part of cortical assemblies that integrate cytoskeletal organization, cell adhesion, and secretion and are subject to microtubule-dependent feedback regulation. Finally, microtubules can mechanically contribute to cell asymmetry by promoting cell elongation, a property that might be important for cells with dense microtubule arrays growing in soft environments.

    更新日期:2019-11-18
  • Fat/Dachsous family cadherins in cell and tissue organisation
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-11-15
    Alexander D. Fulford, Helen McNeill

    Precisely controlled organisation at the cellular and tissue level is crucial to establish and maintain complex organisms. The atypical cadherins Fat (Ft), Fat2 and Dachsous (Ds) contribute to this organisation by regulating growth and planar cell polarity. Here we describe the recent advances in understanding how these large cadherins coordinate these processes, and discuss additional progress extending their function in regulation of microtubules, migration and disease.

    更新日期:2019-11-18
  • Novel approaches to link apicobasal polarity to cell fate specification
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-11-12
    Fumio Motegi, Nicolas Plachta, Virgile Viasnoff

    Understanding the development of apicobasal polarity (ABP) is a long-standing problem in biology. The molecular components involved in the development and maintenance of APB have been largely identified and are known to have ubiquitous roles across organisms. Our knowledge of the functional consequences of ABP establishment and maintenance is far less comprehensive. Recent studies using novel experimental approaches and cellular models have revealed a growing link between ABP and the genetic program of cell lineage. This mini-review describes some of the most recent advances in this new field, highlighting examples from Caenorhabditis elegans and mouse embryos, human pluripotent stem cells, and epithelial cells. We also speculate on the most interesting and challenging avenues that can be explored.

    更新日期:2019-11-13
  • Where does asymmetry come from? Illustrating principles of polarity and asymmetry establishment in Drosophila neuroblasts
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-11-04
    Nicolas Loyer, Jens Januschke

    Asymmetric cell division (ACD) is the fundamental process through which one cell divides into two cells with different fates. In animals, it is crucial for the generation of cell-type diversity and for stem cells, which use ACD both to self-renew and produce one differentiating daughter cell. One of the most prominent model systems of ACD, Drosophila neuroblasts, relies on the PAR complex, a conserved set of proteins governing cell polarity in animals. Here, we focus on recent advances in our understanding of the mechanisms that control the orientation of the neuroblast polarity axis, how the PAR complex is positioned, and how its activity may regulate division orientation and cell fate determinant localization and discuss how important findings about the composition polarity complexes in other models may apply to neuroblasts.

    更新日期:2019-11-04
  • Editorial overview: Signaling dynamics moving to the nanoscale.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-04-14
    Wouter H Moolenaar,Tamás Balla

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Feeling the force: formin's role in mechanotransduction.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-01-15
    Dennis Zimmermann,David R Kovar

    Fundamental cellular processes such as division, polarization, and motility require the tightly regulated spatial and temporal assembly and disassembly of the underlying actin cytoskeleton. The actin cytoskeleton has been long viewed as a central player facilitating diverse mechanotransduction pathways due to the notion that it is capable of receiving, processing, transmitting, and generating mechanical stresses. Recent work has begun to uncover the roles of mechanical stresses in modulating the activity of key regulatory actin-binding proteins and their interactions with actin filaments, thereby controlling the assembly (formin and Arp2/3 complex) and disassembly (ADF/Cofilin) of actin filament networks. In this review, we will focus on discussing the current molecular understanding of how members of the formin protein family sense and respond to forces and the potential implications for formin-mediated mechanotransduction in cells.

    更新日期:2019-11-01
  • Nuclear positioning as an integrator of cell fate.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2018-12-30
    Maria Almonacid,Marie-Emilie Terret,Marie-Hélène Verlhac

    Cells are the building units of living organisms and consequently adapt to their environment by modulating their intracellular architecture, in particular the position of their nucleus. Important efforts have been made to decipher the molecular mechanisms involved in nuclear positioning. The LINC complex at the nuclear envelope is a very important part of the molecular connectivity between the cell outside and the intranuclear compartment, and thus emerged as a central player in nuclear mechanotransduction. More recent concepts in nuclear mechanotransduction came from studies involving nuclear confined migration, compression or swelling. Also, the effect of nuclear mechanosensitive properties in driving cell differentiation raises the question of nuclear mechanotransduction and gene expression and recent efforts have been done to tackle it, even though it remains difficult to address in a direct manner. Eventually, an original mechanism of nucleus positioning, mechanotransduction and regulation of gene expression in the non-adherent, non-polarized mouse oocyte, highlights the fact that nuclear positioning is an important developmental issue.

    更新日期:2019-11-01
  • Mechanical regulation of genome architecture and cell-fate decisions.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2018-12-17
    G V Shivashankar

    Landmark experiments in vitro showed that somatic cells can be reprogrammed to stem-cells by the constitutive expression of particular transcription factors. However, in vivo cells naturally exhibit de-differentiation and trans-differentiation programs, thereby suggesting that the signals from the local mechanical microenvironment may be sufficient to induce stem-cell state transitions. In this review, we discuss recent evidence for the biophysical regulation of genome architecture and nuclear programs. We start by discussing the coupling between cellular architecture, genome organization and gene expression. We then review the role of biophysical factors in regulating genome architecture and cell-state transitions. Finally, we discuss the molecular basis of cell-state transitions during nuclear reprogramming. Collectively, we highlight the importance of the mechanical regulation of genome organization on cell-fate decisions.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • The replication fork's five degrees of freedom, their failure and genome rearrangements.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2009-11-17
    T Weinert,S Kaochar,H Jones,A Paek,A J Clark

    Genome rearrangements are important in pathology and evolution. The thesis of this review is that the genome is in peril when replication forks stall, and stalled forks are normally rescued by error-free mechanisms. Failure of error-free mechanisms results in large-scale chromosome changes called gross chromosomal rearrangements, GCRs, by the aficionados. In this review we discuss five error-free mechanisms a replication fork may use to overcome blockage, mechanisms that are still poorly understood. We then speculate on how genome rearrangements may occur when such mechanisms fail. Replication fork recovery failure may be an important feature of the oncogenic process. (Feedback to the authors on topics discussed herein is welcome.).

    更新日期:2019-11-01
  • Shugoshin: guardian spirit at the centromere.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2005-10-19
    Yoshinori Watanabe

    A recently emerging protein family, shugoshin, plays a crucial role in the centromeric protection of cohesin, which is responsible for sister chromatid cohesion. This is especially important at the first meiotic division, where cohesin is cleaved by separase only along chromosome arms while the centromeric cohesin must be preserved. In vertebrate cells, arm cohesion is largely lost during prophase and prometaphase in order to facilitate sister chromatid resolution, whereas centromeric cohesion is preserved until the bipolar attachment of sister chromatids is established. Vertebrate shugoshin plays an essential role in protecting centromeric cohesin from prophase dissociation. In yeast, shugoshin also has a crucial role in sensing the loss of tension at kinetochores and in generating the spindle checkpoint signal.

    更新日期:2019-11-01
  • Cell biology of the ESCRT machinery.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2009-06-30
    Phyllis I Hanson,Soomin Shim,Samuel A Merrill

    The ESCRT (endosomal sorting complex required for transport) machinery comprises a set of protein complexes that regulate sorting and trafficking into multivesicular bodies en route to the lysosome. The physical mechanism responsible for generating lumenal vesicles in this pathway is unknown. Here we review recent studies suggesting that components of the ESCRT-III complex drive lumenal vesicle formation and consider possible mechanisms for this reaction.

    更新日期:2019-11-01
  • Two major mechanisms of chromosome organization.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-06-23
    Leonid A Mirny,Maxim Imakaev,Nezar Abdennur

    The spatial organization of chromosomes has long been connected to their polymeric nature and is believed to be important for their biological functions, including the control of interactions between genomic elements, the maintenance of genetic information, and the compaction and safe transfer of chromosomes to cellular progeny. chromosome conformation capture techniques, particularly Hi-C, have provided a comprehensive picture of spatial chromosome organization and revealed new features and elements of chromosome folding. Furthermore, recent advances in microscopy have made it possible to obtain distance maps for extensive regions of chromosomes (Bintu et al., 2018; Nir et al., 2018 [2••,3]), providing information complementary to, and in excellent agreement with, Hi-C maps. Not only has the resolution of both techniques advanced significantly, but new perturbation data generated in the last two years have led to the identification of molecular mechanisms behind large-scale genome organization. Two major mechanisms that have been proposed to govern chromosome organization are (i) the active (ATP-dependent) process of loop extrusion by Structural Maintenance of Chromosomes (SMC) complexes, and (ii) the spatial compartmentalization of the genome, which is likely mediated by affinity interactions between heterochromatic regions (Falk et al., 2019 [76••]) rather than by ATP-dependent processes. Here, we review existing evidence that these two processes operate together to fold chromosomes in interphase and that loop extrusion alone drives mitotic compaction. We discuss possible implications of these mechanisms for chromosome function.

    更新日期:2019-11-01
  • Role of MAPK pathway oncoproteins in thyroid cancer pathogenesis and as drug targets.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2009-02-24
    Jeffrey A Knauf,James A Fagin

    Constitutive activation of MAPK in cancer occurs through activating mutations or overexpression of upstream effectors in the pathway, primarily of genes encoding receptor tyrosine kinases, RAS and BRAF. Arguably, the evidence for MAPK activation is most compelling in thyroid cancers and in melanomas. In this review we discuss the mechanisms of tumor development by oncogenic BRAF in these two cancer cell lineages, since this kinase signals preferentially through this pathway. We describe recent information on the mediators of BRAF-induced tumor initiation and escape from senescence. In addition, we review the biochemical events implicated in cellular growth triggered by oncogenic BRAF and the determinants of oncogene addiction. The biology of thyroid cancers induced by oncogenic BRAF is quite distinct, both in humans and in mice. There is great interest in using these insights to design rational new therapies, for which it will become crucial to understand the determinants of sensitivity and resistance to compounds designed to block the pathway. In thyroid cancer, this interest is further heightened by new information on the role of activated BRAF and MAPK pathway activation in disrupting iodine transport and thyroid hormonogenesis.

    更新日期:2019-11-01
  • Transcriptional targets of sirtuins in the coordination of mammalian physiology.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2008-05-13
    Jerome N Feige,Johan Auwerx

    Sirtuins (Sirts) compose a family of NAD(+)-dependent deacetylases and/or ADP-ribosyltransferases, which have been implicated in aging, metabolism, and tolerance to oxidative stress. Many of the biological processes regulated by Sirts result from the adaptation of complex gene-expression programs to the energetic state of the cell, sensed through NAD(+) levels. To that respect, Sirts, and particularly the founding member of the family Sirt1, have emerged as important regulators of transcription, which they modulate both positively and negatively by targeting histones and transcriptional complex regulatory proteins. This review will focus on recent advances that have started deciphering how mammalian Sirts regulate transcriptional networks and thereby control physiology.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Putting the brakes on the cell cycle: mechanisms of cellular growth arrest.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-06-30
    Lindsey R Pack,Leighton H Daigh,Tobias Meyer

    Precise regulation of cellular proliferation is critical to tissue homeostasis and development, but misregulation leads to diseases of excess proliferation or cell loss. To achieve precise control, cells utilize distinct mechanisms of growth arrest such as quiescence and senescence. The decision to enter these growth-arrested states or proliferate is mediated by the core cell-cycle machinery that responds to diverse external and internal signals. Recent advances have revealed the molecular underpinnings of these cell-cycle decisions, highlighting the unique nature of cell-cycle entry from quiescence, identifying endogenous DNA damage as a quiescence-inducing signal, and establishing how persistent arrest is achieved in senescence.

    更新日期:2019-11-01
  • Intravital microscopy in mammalian multicellular organisms.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-05-28
    Seham Ebrahim,Roberto Weigert

    Imaging subcellular processes in live animals is no longer a dream. The development of Intravital Subcellular Microscopy (ISMic) combined with the astounding repertoire of available mouse models makes it possible to investigate processes such as membrane trafficking in mammalian living tissues under native conditions. This has provided the unique opportunity to answer questions that cannot be otherwise addressed in reductionist model systems and to link cell biology to tissue pathophysiology.

    更新日期:2019-11-01
  • The role of Rab GTPases in the pathobiology of Parkinson' disease.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-05-06
    Luis Bonet-Ponce,Mark R Cookson

    Rab GTPases are key regulators of vesicle-mediated transport and are proposed to play a crucial role in the pathobiology of Parkinson's disease. As membrane trafficking seems to be a relevant pathway altered in Parkinson' disease, understanding the role of Rab GTPases in the disease progression could open a window for therapeutic interventions. In this review, we focus on the recent advances on the role of Rab GTPases in the biology of two main proteins involved in Parkinson's disease: LRRK2 and α-synuclein, given that mutations in their genes (LRRK2 and SNCA) cause familial and sporadic Parkinson's disease.

    更新日期:2019-11-01
  • And three's a party: lysosomes, lipid droplets, and the ER in lipid trafficking and cell homeostasis.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-04-20
    Mike Henne

    Sterols and fatty acids (FAs) are essential lipids that play fundamental roles in membrane dynamics and cellular homeostasis. Synthesized at the endoplasmic reticulum (ER) and cytoplasm, trafficked by proteins, and stored in lipid droplets (LDs), much work has been conducted examining how these lipids are shuttled from one location to another. Recent work has highlighted the importance of inter-organelle crosstalk in the regulation of sterol and FA homeostasis. In particular, three organelles-lysosomes, LDs, and the ER network-function together to regulate sterol subcellular distribution and utilization. This tri-organelle crosstalk also drives adaptions to stress and protects against FA-induced lipotoxicity. Here, we highlight recent work revealing how this unique organelle trio function together. We also discuss how LDs can modulate lysosome signaling to control growth, autophagy, and ER homeostasis.

    更新日期:2019-11-01
  • Chromatin's physical properties shape the nucleus and its functions.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-03-20
    Andrew D Stephens,Edward J Banigan,John F Marko

    The cell nucleus encloses, organizes, and protects the genome. Chromatin maintains nuclear mechanical stability and shape in coordination with lamins and the cytoskeleton. Abnormal nuclear shape is a diagnostic marker for human diseases, and it can cause nuclear dysfunction. Chromatin mechanics underlies this link, as alterations to chromatin and its physical properties can disrupt or rescue nuclear shape. The cell can regulate nuclear shape through mechanotransduction pathways that sense and respond to extracellular cues, thus modulating chromatin compaction and rigidity. These findings reveal how chromatin's physical properties can regulate cellular function and drive abnormal nuclear morphology and dysfunction in disease.

    更新日期:2019-11-01
  • Function and regulation of chromatin insulators in dynamic genome organization.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2019-03-16
    Dahong Chen,Elissa P Lei

    Chromatin insulators are DNA-protein complexes that play a crucial role in regulating chromatin organization. Within the past two years, a plethora of genome-wide conformation capture studies have helped reveal that insulators are necessary for proper genome-wide organization of topologically associating domains, which are formed in a manner distinct from that of compartments. These studies have also provided novel insights into the mechanics of how CTCF/cohesin-dependent loops form in mammals, strongly supporting the loop extrusion model. In combination with single-cell imaging approaches in both Drosophila and mammals, the dynamics of insulator-mediated chromatin interactions are also coming to light. Insulator-dependent structures vary across individual cells and tissues, highlighting the need to study the regulation of insulators in particular temporal and spatial contexts throughout development.

    更新日期:2019-11-01
  • Editorial overview: The cell nucleus: Dynamic interplay of shape and function.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2018-06-06
    Mary Dasso,Beatriz M A Fontoura

    更新日期:2019-11-01
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  • From microbiology to cell biology: when an intracellular bacterium becomes part of its host cell.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2016-06-09
    John P McCutcheon

    Mitochondria and chloroplasts are now called organelles, but they used to be bacteria. As they transitioned from endosymbionts to organelles, they became more and more integrated into the biochemistry and cell biology of their hosts. Work over the last 15 years has shown that other symbioses show striking similarities to mitochondria and chloroplasts. In particular, many sap-feeding insects house intracellular bacteria that have genomes that overlap mitochondria and chloroplasts in terms of size and coding capacity. The massive levels of gene loss in some of these bacteria suggest that they, too, are becoming highly integrated with their host cells. Understanding these bacteria will require inspiration from eukaryotic cell biology, because a traditional microbiological framework is insufficient for understanding how they work.

    更新日期:2019-11-01
  • Editorial overview: The cell nucleus: Plastic, elastic and fantastic.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2016-06-01
    Orna Cohen-Fix,Ulrike Kutay

    更新日期:2019-11-01
  • Multiple mechanisms of 3D migration: the origins of plasticity.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2016-04-16
    Ryan J Petrie,Kenneth M Yamada

    Cells migrate through 3D environments using a surprisingly wide variety of molecular mechanisms. These distinct modes of migration often rely on the same intracellular components, which are used in different ways to achieve cell motility. Recent work reveals that how a cell moves can be dictated by the relative amounts of cell-matrix adhesion and actomyosin contractility. A current concept is that the level of difficulty in squeezing the nucleus through a confining 3D environment determines the amounts of adhesion and contractility required for cell motility. Ultimately, determining how the nucleus controls the mode of cell migration will be essential for understanding both physiological and pathological processes dependent on cell migration in the body.

    更新日期:2019-11-01
  • Finding a place in the SUN: telomere maintenance in a diverse nuclear landscape.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2016-04-12
    Hani Ebrahimi,Julia Promisel Cooper

    Telomeres function in the context of a complex nuclear milieu in which telomeres tend to occupy distinct subnuclear regions. Indeed, regulation of the subnuclear positioning of telomeres is conserved from yeast to human, raising the age-old question: to what extent is location important for function? In mitotically dividing cells, the positioning of telomeres affects their epigenetic state and influences telomere processing and synthesis. In meiotic cells, telomere location is important for homologue pairing, centromere assembly and spindle formation. Here we focus on recent insights into the functions of telomere positioning in maintaining genome integrity.

    更新日期:2019-11-01
  • Protein quality control in the nucleus.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2016-03-26
    Ramon D Jones,Richard G Gardner

    The nucleus is the repository for the eukaryotic cell's genetic blueprint, which must be protected from harm to ensure survival. Multiple quality control (QC) pathways operate in the nucleus to maintain the integrity of the DNA, the fidelity of the DNA code during replication, its transcription into mRNA, and the functional structure of the proteins that are required for DNA maintenance, mRNA transcription, and other important nuclear processes. Although we understand a great deal about DNA and RNA QC mechanisms, we know far less about nuclear protein quality control (PQC) mechanisms despite that fact that many human diseases are causally linked to protein misfolding in the nucleus. In this review, we discuss what is known about nuclear PQC and we highlight new questions that have emerged from recent developments in nuclear PQC studies.

    更新日期:2019-11-01
  • A question of time: tissue adaptation to mechanical forces.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2016-03-06
    Tom Wyatt,Buzz Baum,Guillaume Charras

    While much attention has been focused on the force-generating mechanisms responsible for shaping developing embryos, less is known about the ways in which cells in animal tissues respond to mechanical stimuli. Forces will arise within a tissue as the result of processes such as local cell death, growth and division, but they can also be an indirect consequence of morphogenetic movements in neighbouring tissues or be imposed from the outside, for example, by gravity. If not dealt with, the accumulation of stress and the resulting tissue deformation can pose a threat to tissue integrity and structure. Here we follow the time-course of events by which cells and tissues return to their preferred state following a mechanical perturbation. In doing so, we discuss the spectrum of biological and physical mechanisms known to underlie mechanical homeostasis in animal tissues.

    更新日期:2019-11-01
  • Signalling at membrane contact sites: two membranes come together to handle second messengers.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2016-03-01
    Tim P Levine,Sandip Patel

    It is now clear that many intracellular signals result from multiple membrane-bound compartments acting in concert. Membrane contact sites, regions of close apposition between organelles, have emerged as major points of convergence during signalling, as these are places where material is exchanged. The material exchanged can be either water-insoluble molecules such as membrane lipids that are passed directly between organelles, or ions such as Ca(2+). Here we highlight new insights into the role of contacts in signalling by second messengers, including lipid traffic that underpins re-generation of IP3, the regulation of NAADP and store-operated Ca(2+) signals, and possible involvement in cyclic AMP signalling.

    更新日期:2019-11-01
  • Lipid droplet-organelle interactions: emerging roles in lipid metabolism.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2015-05-20
    Antonio Daniel Barbosa,David B Savage,Symeon Siniossoglou

    Cellular homeostasis depends on the precisely coordinated use of lipids as fuels for energy production, building blocks for membrane biogenesis or chemical signals for intra-cellular and inter-cellular communication. Lipid droplets (LDs) are universally conserved dynamic organelles that can store and mobilize fatty acids and other lipid species for their multiple cellular roles. Increasing evidence suggests that contact zones between LDs and other organelles play important roles in the trafficking of lipids and in the regulation of lipid metabolism. Here we review recent advances regarding the nature and functional relevance of interactions between LDs and other organelles-particularly the endoplasmic reticulum (ER), LDs, mitochondria and vacuoles-that highlight their importance for lipid metabolism.

    更新日期:2019-11-01
  • Membrane contact sites, gateways for lipid homeostasis.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2015-01-09
    Sujoy Lahiri,Alexandre Toulmay,William A Prinz

    Maintaining the proper lipid composition of cellular membranes is critical for numerous cellular processes but mechanisms of membrane lipid homeostasis are not well understood. There is growing evidence that membrane contact sites (MCSs), regions where two organelles come in close proximity to one another, play major roles in the regulation of intracellular lipid composition and distribution. MCSs are thought to mediate the exchange of lipids and signals between organelles. In this review, we discuss how lipid exchange occurs at MCSs and evidence for roles of MCSs in regulating lipid synthesis and degradation. We also discuss how networks of organelles connected by MCSs may modulate cellular lipid homeostasis and help determine organelle lipid composition.

    更新日期:2019-11-01
  • Lipid-dependent regulation of the unfolded protein response.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2014-12-30
    Romain Volmer,David Ron

    Protein folding homeostasis in the lumen of the endoplasmic reticulum is defended by signal transduction pathways that are activated by an imbalance between unfolded proteins and chaperones (so called ER stress). Collectively referred to as the unfolded protein response (UPR) this homeostatic response is initiated by three known ER stress transducers: IRE1, PERK and ATF6. These ER-localised transmembrane (TM) proteins posses lumenal stress sensing domains and cytosolic effector domains that collectively activate a gene expression programme regulating the production of proteins involved in the processing and maturation of secreted proteins that enter the ER. However, beyond limiting unfolded protein stress in the ER the UPR has important connections to lipid metabolism that are the subject of this review.

    更新日期:2019-11-01
  • Mitochondrial pyruvate import and its effects on homeostasis.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2014-12-03
    Benoît Vanderperre,Tom Bender,Edmund R S Kunji,Jean-Claude Martinou

    Pyruvate metabolism plays a pivotal role in cell homeostasis and energy production. Pyruvate, the end product of glycolysis, is either catabolized in the cytosol, or enters into mitochondria to promote oxidative phosphorylation. The import of pyruvate into mitochondria requires a specific carrier in the inner mitochondrial membrane, the mitochondrial pyruvate carrier (MPC), whose identity was only recently discovered. Here we report our current knowledge of the structure and function of the MPC and we describe how dysfunction of the MPC could participate in various pathologies, including type 2 diabetes and cancer.

    更新日期:2019-11-01
  • Editorial overview: Cell organelles.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2014-07-27
    David K Banfield,Will Prinz

    更新日期:2019-11-01
  • New paradigms in the establishment and maintenance of gradients during directed cell migration.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2014-06-25
    Ritankar Majumdar,Michael Sixt,Carole A Parent

    Directional guidance of migrating cells is relatively well explored in the reductionist setting of cell culture experiments. Here spatial gradients of chemical cues as well as gradients of mechanical substrate characteristics prove sufficient to attract single cells as well as their collectives. How such gradients present and act in the context of an organism is far less clear. Here we review recent advances in understanding how guidance cues emerge and operate in complex physiological settings.

    更新日期:2019-11-01
  • Mechanisms shaping cell membranes.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2014-04-22
    Michael M Kozlov,Felix Campelo,Nicole Liska,Leonid V Chernomordik,Siewert J Marrink,Harvey T McMahon

    Membranes of intracellular organelles are characterized by large curvatures with radii of the order of 10-30nm. While, generally, membrane curvature can be a consequence of any asymmetry between the membrane monolayers, generation of large curvatures requires the action of mechanisms based on specialized proteins. Here we discuss the three most relevant classes of such mechanisms with emphasis on the physical requirements for proteins to be effective in generation of membrane curvature. We provide new quantitative estimates of membrane bending by shallow hydrophobic insertions and compare the efficiency of the insertion mechanism with those of the protein scaffolding and crowding mechanisms.

    更新日期:2019-11-01
  • Melanosome transfer: it is best to give and receive.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2014-03-26
    Xufeng Wu,John A Hammer

    The pigmentation of skin and hair in mammals is driven by the creation within melanocytes of melanosomes, a specialized pigment-producing organelle, and the subsequent intercellular transfer of this organelle to keratinocytes. This latter process is absolutely required for visible pigmentation and effective photo-protection because it serves to disperse the pigment in skin and hair. Therefore, the transfer of melanosomes from the melanocyte to the keratinocyte is as important for the biological endpoint of mammalian pigmentation as the biogenesis of this fascinating organelle. Here we review new findings that shed light on, and raise additional questions about, the mechanism of this enigmatic process.

    更新日期:2019-11-01
  • Changes in cell and tissue organization in cancer of the breast and colon.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2014-02-18
    Lindsay Hinck,Inke Näthke

    Most cancers arise in epithelia, the tissue type that lines all body cavities. The organization of epithelia enables them to act as a barrier and perform vectorial transport of molecules between body compartments. Crucial for their organization and function is a highly specialized network of cell adhesion and polarity proteins aligned along the apical-basal axis. Comparing breast and intestinal tissue as examples of common cancer sites, reveals an important contribution of polarity proteins to the initiation and progression of cancer. Defects in polarity are induced directly by mutations in polarity proteins, but also indirectly by changes in the expression of specific microRNAs and altered transcriptional programs that drive cellular differentiation from epithelial to more mesenchymal characteristics. The latter is particularly important in the metastatic process.

    更新日期:2019-11-01
  • Novel insights into G protein and G protein-coupled receptor signaling in cancer.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2014-02-11
    Morgan O'Hayre,Maria S Degese,J Silvio Gutkind

    G protein-coupled receptors (GPCRs) play a central role in signal transmission, thereby controlling many facets of cellular function. Overwhelming evidence now implicates GPCRs, G proteins and their downstream signaling targets in cancer initiation and progression, where they can influence aberrant cell growth and survival, largely through activation of AKT/mTOR, MAPKs, and Hippo signaling pathways. GPCRs also play critical roles in the invasion and metastasis of cancer cells via activation of Rho GTPases and cytoskeletal changes, and angiogenesis to supply the tumor with nutrients and provide routes for metastasis. Lastly, GPCRs contribute to the establishment and maintenance of a permissive tumor microenvironment. Understanding GPCR involvement in cancer malignancy may help identify novel therapeutic opportunities for cancer prevention and treatment.

    更新日期:2019-11-01
  • Mitosis and apoptosis: how is the balance set?
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2013-07-31
    Caroline H Topham,Stephen S Taylor

    Anti-mitotic agents are used extensively during cancer chemotherapy. These agents target microtubules and thus block mitotic progression by activating the spindle assembly checkpoint. Following a prolonged mitotic arrest, cells either die in mitosis via apoptosis, or exit mitosis without dividing and survive, a process known as slippage. What dictates the balance between these two fates is unclear, but recent advances highlight the importance of the pro-survival Bcl2 family, with Mcl1 degradation emerging as a key determinant of mitotic cell fate. Here we review these advances, with a view towards identifying how the balance between apoptosis and slippage can be tipped in favour of death. This in turn may open up new opportunities to sensitize cancer cells to anti-mitotic agents.

    更新日期:2019-11-01
  • Metabolic regulation of the cell cycle.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2013-07-31
    In Hye Lee,Toren Finkel

    There is a growing appreciation that metabolic signals are integrated and coupled to cell cycle progression. However, the molecular wiring that connects nutrient availability, biosynthetic intermediates and energetic balance to the core cell cycle machinery remains incompletely understood. In this review, we explore the recent progress in this area with particular emphasis on how nutrient and energetic status is sensed within the cell to ultimately regulate cell growth and division. The role these pathways play in normal cell function including stem cell biology is also discussed. Furthermore, we describe the growing appreciation that dysregulation of these pathways might contribute to a variety of pathological conditions including metabolic diseases and tumor formation.

    更新日期:2019-11-01
  • Dimensions in cell migration.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2013-07-16
    Andrew D Doyle,Ryan J Petrie,Matthew L Kutys,Kenneth M Yamada

    The importance of cell migration for both normal physiological functions and disease processes has been clear for the past 50 years. Although investigations of two-dimensional (2D) migration in regular tissue culture have elucidated many important molecular mechanisms, recent evidence suggests that cell migration depends profoundly on the dimensionality of the extracellular matrix (ECM). Here we review a number of evolving concepts revealed when cell migration is examined in different dimensions.

    更新日期:2019-11-01
  • Guiding cell migration by tugging.
    Curr. Opin. Cell Biol. (IF 8.233) Pub Date : 2013-07-09
    Sergey V Plotnikov,Clare M Waterman

    The ability of cells to move directionally toward areas of stiffer extracellular matrix (ECM) via a process known as 'durotaxis' is thought to be critical for development and wound healing, but durotaxis can also drive cancer metastasis. Migration is driven by integrin-mediated focal adhesions (FAs), protein assemblies that couple contractile actomyosin bundles to the plasma membrane, transmit force generated by the cytoskeleton to the ECM, and convert the mechanical properties of the microenvironment into biochemical signals. To probe the stiffness of the ECM, motile fibroblasts modulate FA mechanics on the nanoscale and exert forces that are reminiscent of repeated tugging on the ECM. Within a single cell, all FAs tug autonomously and thus act as local rigidity sensors, allowing discernment of differences in the extracellular matrix rigidity at high spatial resolution. In this article, we review current advances that may shed light on the mechanism of traction force fluctuations within FAs. We also examine plausible downstream effectors of tugging forces which may regulate cytoskeletal and FA dynamics to guide cell migration in response to ECM stiffness gradients.

    更新日期:2019-11-01
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