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  • Downregulation of miR-17-92 cluster by PERK fine-tunes unfolded protein response mediated apoptosis
    bioRxiv. Cell Biol. Pub Date : 2020-10-26
    Danielle Read; Ananya Gupta; Karen Cawley; Laura Fontana; Patrizia Agostinis; Afshin Samali; Sanjeev Gupta

    An important event in the unfolded protein response (UPR) is the activation of the endoplasmic reticulum kinase PERK (EIF2AK3). The PERK signalling branch first mediates a prosurvival response, which switches into a proapoptotic response upon prolonged ER stress. However, the molecular mechanisms of PERK-mediated cell death are not well understood. Here we show that expression of the primary miR-17-92

    更新日期:2020-10-27
  • Non-apoptotic enteroblast-specific role of the initiator caspase Dronc for development and homeostasis of the Drosophila intestine
    bioRxiv. Cell Biol. Pub Date : 2020-10-26
    Jillian L Lindblad; Meghana Tare; Alla Amcheslavsky; Alicia Shields; Andreas Bergmann

    The initiator caspase Dronc is the only CARD-domain containing caspase in Drosophila and is essential for apoptosis. Here, we report that homozygous dronc mutant adult animals are short-lived due to the presence of a poorly developed, defective and leaky intestine. Interestingly, this mutant phenotype can be significantly rescued by enteroblast-specific expression of dronc+ in dronc mutant animals

    更新日期:2020-10-27
  • AP-4 mediates vesicular transport of the 2-AG endocannabinoid producing enzyme DAGLB
    bioRxiv. Cell Biol. Pub Date : 2020-10-25
    Alexandra K Davies; Marvin Ziegler; Hellen Jumo; Wardiya Afshar Saber; Darius Ebrahimi-Fakhari; Georg H H Borner

    The adaptor protein complex AP-4 mediates anterograde axonal transport and is essential for axon health. AP-4-deficient patients suffer from a severe neurological disorder, which encompasses neurodevelopmental and neurodegenerative features. While impaired autophagy has been suggested to account for axon degeneration in AP-4 deficiency, axon growth defects occur through an unknown mechanism. Here we

    更新日期:2020-10-27
  • Oxidants are dispensable for HIF1α stability in hypoxia
    bioRxiv. Cell Biol. Pub Date : 2020-10-25
    Amit Kumar; Manisha Vaish; Saravanan S. Karuppagounder; Irina Gazaryan; John W. Cave; Anatoly A. Starkov; Elizabeth T. Anderson; Sheng Zhang; John T. Pinto; Austin Rountree; Wang Wang; Ian R. Sweet; Rajiv Ram Ratan

    Hypoxic adaptation mediated by HIF transcription factors has been shown to require mitochondria. Current models suggest that mitochondria regulate oxygen sensor (HIF prolyl hydroxylase) activity and HIF1α stability during hypoxia by either increasing mitochondrial peroxide as a second messenger or by serving as oxygen consumers that enhance the kinetics of cytoplasmic oxygen reduction. Here, we address

    更新日期:2020-10-27
  • Adhesion-mediated mechanosignaling forces mitohormesis
    bioRxiv. Cell Biol. Pub Date : 2020-10-25
    Kevin M Tharp; Ryo Higuchi-Sanabria; Greg Timblin; Breanna Ford; Carlos Garzon-Coral; Catherine Schneider; Jonathon M Muncie; Connor Stashko; Joseph Daniele; Andrew S Moore; Phillip Frankino; Sagar Manoli; Hao Shao; Alicia L Richards; Kuei-Ho Chen; Gregory M Ku; Marc Hellerstein; Kaoru Saijo; Jason Gestwicki; Daniel K Nomura; Nevan J Krogan; Alex Dunn; Danielle Swaney; Andrew Dillin; Valerie M Weaver

    Mitochondria control eukaryotic cell fate by producing the energy needed to support life and the signals required to execute programmed cell death. The biochemical milieu is known to affect mitochondrial function and contribute to the dysfunctional mitochondrial phenotypes implicated in cancer and the morbidities of ageing. However, the physical characteristics of the extracellular matrix are also

    更新日期:2020-10-27
  • The papain-like protease of coronaviruses cleaves ULK1 to disrupt host autophagy
    bioRxiv. Cell Biol. Pub Date : 2020-10-25
    Yasir Mohamud; Yuan Chao Xue; Huitao Liu; Chen Seng Ng; Amirhossein Bahreyni; Eric Jan; Honglin Luo

    The ongoing pandemic of COVID-19 alongside the outbreaks of SARS in 2003 and MERS in 2012 underscore the significance to understand betacoronaviruses as a global health challenge. SARS-CoV-2, the etiological agent for COVID-19, has infected more than 29 million individuals worldwide with nearly ~1 million fatalities. Understanding how SARS-CoV-2 initiates viral pathogenesis is of the utmost importance

    更新日期:2020-10-27
  • O-GlcNAc modification of nuclear pore complexes accelerates bi-directional transport
    bioRxiv. Cell Biol. Pub Date : 2020-10-24
    Tae Yeon Yoo; Timothy J Mitchison

    Macromolecular transport across the nuclear envelope depends on facilitated diffusion through nuclear pore complexes (NPCs). The interior of NPCs contains a permeability barrier made of phenylalanine-glycine (FG) repeat domains that selectively facilitates the permeation of cargoes bound to nuclear transport receptors (NTRs). FG repeats in NPC are a major site of O-linked N-acetylglucosamine (O-GlcNAc)

    更新日期:2020-10-27
  • Real-time luminescence assay for cytoplasmic cargo delivery of extracellular vesicles
    bioRxiv. Cell Biol. Pub Date : 2020-10-24
    Masaharu Somiya; Shun'ichi Kuroda

    Extracellular vesicles (EVs) have been considered to deliver biological cargos between cells and mediate intercellular communication. However, the mechanisms that underlie the biological process of EV uptake and cytoplasmic cargo release in recipient cells are largely unknown. Quantitative and real-time assays for assessment of the cargo delivery efficiency inside recipient cells have not been feasible

    更新日期:2020-10-27
  • The surface of lipid droplets constitutes a barrier for endoplasmic reticulum residential integral membrane spanning proteins
    bioRxiv. Cell Biol. Pub Date : 2020-10-23
    Rasha Khaddaj; Muriel Mari; Stephanie Cottier; Fulvio Reggiori; Roger Schneiter

    Lipid droplets (LDs) are globular subcellular structures that mainly serve to store energy in form of neutral lipids, particularly triacylglycerols and steryl esters. LDs are closely associated with the membrane of the endoplasmic reticulum (ER), and are limited by a monolayer membrane of phospholipids harboring a specific set of proteins. Most of these proteins associate with LDs through either an

    更新日期:2020-10-27
  • Concerted action of kinesins KIF5B and KIF13B promotes efficient secretory vesicle transport to microtubule plus ends
    bioRxiv. Cell Biol. Pub Date : 2020-10-23
    Andrea Serra-Marques; Maud Martin; Eugene A Katrukha; Ilya Grigoriev; Cathelijn A.E. Peeters; Qingyang Liu; Peter Jan Hooikaas; Yao Yao; Veronika Solianova; Ihor Smal; Lotte B. Pedersen; Erik Meijering; Lukas C. Kapitein; Anna Akhmanova

    Intracellular transport relies on multiple kinesins, but it is poorly understood which kinesins are present on particular cargos, what their contributions are and whether they act simultaneously on the same cargo. Here, we show that Rab6-positive secretory vesicles are transported from the Golgi apparatus to the cell periphery by kinesin-1 KIF5B and kinesin-3 KIF13B, which determine the location of

    更新日期:2020-10-27
  • Protein hyperacylation links mitochondrial dysfunction with nuclear organization
    bioRxiv. Cell Biol. Pub Date : 2020-10-23
    John A Smestad; Micah McCauley; Matthew Amato; Yuning Xiong; Juan Liu; Yi-Cheng Sin; Jake Ellingson; Yue Chen; Fatimah Al Khazal; Brandon Wilbanks; Jeong-Heon Lee; Tamas Ordog; Ioulia Rouzina; Mark C. Williams; Jason Locasale; Louis J Maher

    Cellular metabolism is linked to epigenetics, but the biophysical effects of metabolism on chromatin structure and implications for gene regulation remain largely unknown. Here, using a broken tricarboxylic acid (TCA) cycle and disrupted electron transport chain (ETC) exemplified by succinate dehydrogenase subunit C (SDHC) deficiency, we investigated the effects of metabolism on chromatin architecture

    更新日期:2020-10-27
  • A Wnt5a-Cdc42 axis controls aging and rejuvenation of hair-follicle stem cells
    bioRxiv. Cell Biol. Pub Date : 2020-10-23
    Rajiv L Tiwari; Pratibha Mishra; Nicola Martin; Nikhil Oommen George; Vadim Sakk; Karin Soller; Kodandaramireddy Nalapareddy; Kalpana Nattamai; Karin Scharffetter-Kochanek; Maria Carolina Florian; Hartmut Geiger

    Normal hair growth occurs in cycles, comprising growth (anagen), cessation (catagen) and rest (telogen). Upon aging, the initiation of anagen is significantly delayed, which results in impaired hair regeneration. Hair regeneration is driven by hair follicle stem cells (HFSCs). We show here that aged HFSCs present with a decrease in canonical Wnt signaling and a shift towards non-canonical Wnt5a driven

    更新日期:2020-10-27
  • NUPR1 protects liver from lipotoxic injury by improving the endoplasmic reticulum stress response
    bioRxiv. Cell Biol. Pub Date : 2020-10-23
    Maria Teresa Borrello; Maria Rita Emma; Angela Listi; Marion Rubis; Sergiu Coslet; Giuseppa Augello; Antonella Cusimano; Daniela Cabibi; Rossana Porcasi; Lydia Giannitrapani; Maurizio Soresi; Gianni Pantuso; Karen Blyth; Giuseppe Montalto; Christopher Pin; Melchiorre Cervello; Juan Iovanna

    Objective: Non-alcoholic fatty liver (NAFL) disease and related hepatic syndromes affect up to one third of the adult population in industrialised and developing countries. However, the molecular mechanisms underlying NAFL etiology remain elusive. Nuclear Protein 1 (NUPR1) expression increases upon cell injury in all organs including the liver. Recently, we report NUPR1 actively participates in activation

    更新日期:2020-10-27
  • Cortical myosin minifilaments orchestrate the arrangement of microridge protrusions on epithelial cell surfaces
    bioRxiv. Cell Biol. Pub Date : 2020-10-23
    Aaron P. van Loon; Ivan S. Erofeev; Andrew B. Goryachev; Alvaro Sagasti

    Actin-based protrusions vary in morphology, stability, and arrangement on cell surfaces. Microridges are laterally-elongated protrusions arranged in maze-like patterns on mucosal epithelial cells that rearrange dynamically by fission and fusion. To characterize how microridges mature and investigate the mechanisms driving fission and fusion, we imaged microridges in the maturing skin of zebrafish larvae

    更新日期:2020-10-27
  • SARS-CoV-2 receptor Angiotensin I-Converting Enzyme type 2 (ACE2) is expressed in human pancreatic β-cells and in the human pancreas microvasculature
    bioRxiv. Cell Biol. Pub Date : 2020-10-23
    Daniela Fignani; Giada Licata; Noemi Brusco; Laura Nigi; Giuseppina E. Grieco; Lorella Marselli; Lut Overbergh; Conny Gysemans; Maikel L. Colli; Piero Marchetti; Chantal Mathieu; Decio L. Eizirik; Guido Sebastiani; Francesco Dotta

    Increasing evidence demonstrated that the expression of Angiotensin I-Converting Enzyme type 2 (ACE2), is a necessary step for SARS-CoV-2 infection permissiveness. In the light of the recent data highlighting an association between COVID-19 and diabetes, a detailed analysis aimed at evaluating ACE2 expression pattern distribution in human pancreas is still lacking. Here, we took advantage of INNODIA

    更新日期:2020-10-27
  • Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction
    bioRxiv. Cell Biol. Pub Date : 2020-10-22
    Kendall J. Condon; Jose M. Orozco; Charles H. Adelmann; Jessica B. Spinelli; Pim W. van der Helm; Justin M. Roberts; Tenzin Kunchok; David M. Sabatini

    In mammalian cells, nutrients and growth factors signal through an array of upstream proteins to regulate the mTORC1 growth control pathway. Because the full complement of these proteins has not been systematically identified, we developed a FACS-based CRISPR-Cas9 genetic screening strategy to pinpoint genes that regulate mTORC1 activity. Along with almost all known positive components of the mTORC1

    更新日期:2020-10-27
  • Mitochondrial fission governed by Drp1 regulates exogenous fatty acid usage and storage
    bioRxiv. Cell Biol. Pub Date : 2020-10-22
    Jae Eun Song; Tiago C. Alves; Bernardo Stutz; Matija Sestan-Pesa; Nicole Kilian; Sabrina Diano; Richard G. Kibbey; Tamas L. Horvath

    The bioenergetic function of mitochondrial fission is associated with uncoupled respiration or elimination of damaged mitochondria to maintain a healthy mitochondrial population. In the presence of a high abundance of exogenous fatty acids, cells can either store fatty acids in lipid droplets or oxidize them in mitochondria. Even though carnitine palmitoyltransferase-1 (CPT1) controls the respiratory

    更新日期:2020-10-27
  • A Deep Learning Pipeline for Nucleus Segmentation
    bioRxiv. Cell Biol. Pub Date : 2020-10-22
    George Zaki; Prabhakar R. Gudla; Kyunghun Lee; Justin Kim; Laurent Ozbun; Sigal Shachar; Manasi Gadkari; Jing Sun; Iain D.C. Fraser; Luis M. Franco; Tom Misteli; Gianluca Pegoraro

    Deep learning is rapidly becoming the technique of choice for automated segmentation of nuclei in biological image analysis workflows. In order to evaluate the feasibility of training nuclear segmentation models on small, custom annotated image datasets that have been augmented, we have designed a computational pipeline to systematically compare different nuclear segmentation model architectures and

    更新日期:2020-10-27
  • Conditional targeting of phosphatidylserine decarboxylase to lipid droplets
    bioRxiv. Cell Biol. Pub Date : 2020-10-22
    Santosh Kumar; Chandramohan Chitraju; Robert Farese; Tobias Walther; Christopher G. Burd

    Phosphatidylethanolamine is an abundant component of most cellular membranes whose physical and chemical properties modulate multiple aspects of organelle membrane dynamics. An evolutionarily ancient mechanism for producing phosphatidylethanolamine is to decarboxylate phosphatidylserine and the enzyme catalyzing this reaction, phosphatidylserine decarboxylase, localizes to the inner membrane of the

    更新日期:2020-10-27
  • Fluorescent tagging of Plasmodium circumsporozoite protein allows imaging of sporozoite formation but blocks egress from oocysts
    bioRxiv. Cell Biol. Pub Date : 2020-10-22
    Mirko Singer; Friedrich Frischknecht

    The circumsporozoite protein, CSP is the major surface protein of Plasmodium sporozoites, the form of malaria parasites transmitted by mosquitoes. CSP is involved in sporozoite formation within and egress from oocysts, entry into mosquito salivary glands and mammalian liver as well as migration in the skin. Antibodies against CSP can stop infection prior to the first round of parasite replication in

    更新日期:2020-10-27
  • Integrated Single Cell Atlas of Endothelial Cells of the Human Lung
    bioRxiv. Cell Biol. Pub Date : 2020-10-22
    Jonas C. Schupp; Taylor S. Adams; Carlos Cosme; Micha Sam Brickman Raredon; Norihito Omote; Sergio Poli De Frias; Kadi-Ann Rose; Edward Manning; Maor Sauler; Giuseppe DeIuliis; Farida Ahangari; Nir Neumark; Yifan Yuan; Arun C. Habermann; Austin J. Gutierrez; Linh T. Bui; Kerstin B. Meyer; Martijn C. Nawijn; Sarah A. Teichmann; Nicholas E. Banovich; Jonathan A. Kropski; Laura E. Niklason; Dana Pe’er;

    Background: Despite its importance in health and disease, the cellular diversity of the lung endothelium has not been systematically characterized in humans. Here we provide a reference atlas of human lung endothelial cells (ECs), to facilitate a better understanding of the phenotypic diversity and composition of cells comprising the lung endothelium, both in health and disease. Methods: We reprocessed

    更新日期:2020-10-27
  • Nuclear deformation causes DNA damage by increasing replication stress
    bioRxiv. Cell Biol. Pub Date : 2020-10-21
    Pragya Shah; Chad M. Hobson; Svea Cheng; Marshall Colville; Matthew Paszek; Richard Superfine; Jan Lammerding

    Cancer metastasis, i.e., the spreading of tumor cells from the primary tumor to distant organs, is responsible for the vast majority of cancer deaths. In the process, cancer cells migrate through narrow interstitial spaces substantially smaller in cross-section than the cell. During such confined migration, cancer cells experience extensive nuclear deformation, nuclear envelope rupture, and DNA damage

    更新日期:2020-10-27
  • Characterization of Constitutive macro-ER-phagy
    bioRxiv. Cell Biol. Pub Date : 2020-10-21
    Zhanna Lipatova; Valeriya Gyurkovska; Sarah F. Zhao; Nava Segev

    Thirty percent of all cellular proteins are inserted into the endoplasmic reticulum (ER), which spans throughout the cytoplasm. Two well-established stress-induced pathways ensure quality control (QC) at the ER: ER-phagy and ER-associated degradation (ERAD), which shuttle cargo for degradation to the lysosome and proteasome, respectively. In contrast, not much is known about constitutive ER-phagy.

    更新日期:2020-10-27
  • Direct visualization of epithelial microvilli biogenesis
    bioRxiv. Cell Biol. Pub Date : 2020-10-21
    Isabella M. Gaeta; Leslie M. Meenderink; Meagan M. Postema; Caroline S. Cencer; Matthew J. Tyska

    Microvilli are actin bundle supported surface protrusions that play essential roles in diverse epithelial cell functions. To develop our understanding of microvilli biogenesis, we used live imaging to directly visualize protrusion growth at early stages of epithelial differentiation. Time-lapse data revealed that an 'initiation complex' enriched in EPS8 and IRTKS appears at future sites of microvillus

    更新日期:2020-10-27
  • Misoprostol Treatment Prevents Hypoxia-Induced Cardiac Dysfunction, Aberrant Cardiomyocyte Mitochondrial Dynamics and Permeability Transition Through Bnip3 Phosphorylation
    bioRxiv. Cell Biol. Pub Date : 2020-10-21
    Matthew D. Martens; Nivedita Seshadri; Lucas Nguyen; Donald Chapman; Elizabeth S. Henson; Bo Xiang; Arielys Mendoza; Sunil Rattan; Spencer B. Gibson; Ayesha Saleem; Grant M. Hatch; Christine A. Doucette; Jason M. Karch; Vernon W. Dolinsky; Ian M. Dixon; Adrian R. West; Christof Rampitsch; Joseph W. Gordon

    Systemic hypoxia, a major complication associated with reduced gestational time, affects more 60% of preterm infants and is a known driver of hypoxia-induced Bcl-2-like 19kDa-interacting protein 3 (Bnip3) expression in the neonatal heart. At the level of the cardiomyocyte, Bnip3 activity plays a prominent role in the evolution of necrotic cell death, disrupting subcellular calcium homeostasis and initiating

    更新日期:2020-10-27
  • Mammalian-unique eIF4E2 maintains GSK3β proline kinase activity to resist senescence against hypoxia
    bioRxiv. Cell Biol. Pub Date : 2020-10-21
    Min zhang; Lei Sun; Dong He; Jian Chen; Zhiqiang Dong; Huiting Liang; Yu Cao; Bingcheng Cai; He Yang

    Cellular senescence is a stable state of cell cycle arrest elicited by various stresses. Hypoxia modulates senescence, but its consequences and implications in living organisms remains unknown. Here we identified the eIF4E2-GSK3β pathway regulated by hypoxia to maintain p53 proline-directed phosphorylation (S/T-P) to prevent senescence. We previously knew that GSK3β activates p53 translation through

    更新日期:2020-10-27
  • Mechanosensitive calcium signaling in filopodia
    bioRxiv. Cell Biol. Pub Date : 2020-10-21
    Artem K. Efremov; Mingxi Yao; Michael P. Sheetz; Alexander D. Bershadsky; Boris Martinac; Jie Yan

    Filopodia are ubiquitous membrane projections that play crucial role in guiding cell migration on rigid substrates and through extracellular matrix by utilizing yet unknown mechanosensing molecular pathways. As recent studies show that Ca2+ channels localized to filopodia play an important role in regulation of their formation and since some Ca2+ channels are known to possess mechanosensing properties

    更新日期:2020-10-27
  • Regulated compartmentalization of enzymes in Golgi by GRASP55 controls cellular glycosphingolipid profile and function
    bioRxiv. Cell Biol. Pub Date : 2020-10-21
    Prathyush Pothukuchi; Ilenia Agliarulo; Marinella Pirozzi; Riccardo Rizzo; Domenico Russo; Gabriele Turacchio; Julian Nüchel; Jia-Shu Yang; Charlotte Julie Caroline Gehin; Laura Capolupo; Maria Jose Hernandez-Corbacho; Ansuman Biswas; Giovanna Vanacore; Nina Dathan; Takahiro Nitta; Petra Henklein; Mukund Thattai; Jin-Ichi Inokuchi; Victor W. Hsu; Markus Plomann; Lina M. Obeid; Yusuf A. Hannun; Alberto

    Glycans are important regulators of cell and organismal physiology. This requires that the glycan biosynthesis be controlled to achieve specific cellular glycan profiles. Glycans are assembled in the Golgi apparatus on secretory cargoes that traverse it. The mechanisms by which the Golgi apparatus ensures cell- and cargo-specific glycosylation remain obscure. We investigated how the Golgi apparatus

    更新日期:2020-10-27
  • Using single-cell entropy to describe the dynamics of reprogramming and differentiation of induced pluripotent stem cells
    bioRxiv. Cell Biol. Pub Date : 2020-10-21
    Yusong Ye; Zhuoqin Yang; Meixia Zhu; Jinzhi Lei

    Induced pluripotent stem cells (iPSCs) provide a great model to study the process of stem cell reprogramming and differentiation. Single-cell RNA sequencing (scRNA-seq) enables us to investigate the reprogramming process at single-cell level. Here, we introduce single-cell entropy (scEntropy) as a macroscopic variable to quantify the cellular transcriptome from scRNA-seq data during reprogramming and

    更新日期:2020-10-27
  • A novel Golgi-associated Vangl2 translational variant required for PCP regulation in vertebrates
    bioRxiv. Cell Biol. Pub Date : 2020-10-20
    Alexandra Walton; Diego Revinski; Arnauld Sergé; Stéphane Audebert; Luc Camoin; Tania M Puvirajesinghe; Daniel Isnardon; Sylvie Marchetto; Laurent Kodjabachian; Eric Bailly; Jean-Paul Borg

    First described in Drosophila melanogaster, planar cell polarity (PCP) is a developmental process essential for embryogenesis and development of polarized structures in Metazoans. This signaling pathway involves a set of evolutionarily conserved genes encoding transmembrane (Vangl, Frizzled, Celsr) and cytoplasmic (Prickle, Dishevelled) molecules. Vangl2 is of major importance in embryonic development

    更新日期:2020-10-27
  • Toll-9 interacts with Toll-1 to mediate a feedback loop during apoptosis-induced proliferation in Drosophila
    bioRxiv. Cell Biol. Pub Date : 2020-10-20
    Alicia Shields; Alla Amcheslavsky; Elizabeth Brown; Yingchao Nie; Takahiro Tanji; Y. Tony Ip; Andreas Bergmann

    Drosophila Toll-1 and all mammalian Toll-like receptors regulate innate immunity. However, the functions of the remaining eight Toll-related proteins in Drosophila are not fully understood. Here, we show that Drosophila Toll-9 is necessary and sufficient for a special form of compensatory proliferation after apoptotic cell loss (undead apoptosis-induced proliferation (AiP)). Mechanistically, for AiP

    更新日期:2020-10-27
  • Spatial Heterogeneity of Delta-like 4 Within a Multinucleated Niche Cell Maintains Muscle Stem Cell Diversity
    bioRxiv. Cell Biol. Pub Date : 2020-10-20
    Susan Eliazer; Xuefeng Sun; Andrew S. Brack

    The quiescent muscle stem cell (QSC) pool is heterogeneous and generally characterized by the presence and levels of intrinsic myogenic transcription factors. Whether extrinsic factors maintain the diversity of states across the QSC pool remains unknown. The muscle fiber is a multinucleated syncytium that serves as a niche to QSCs, raising the possibility that the muscle fiber regulates the diversity

    更新日期:2020-10-27
  • A lamin A/C variant causing striated muscle disease provides insights into filament organization
    bioRxiv. Cell Biol. Pub Date : 2020-10-20
    Rafael Kronenberg-Tenga; Meltem Tatli; Matthias Eibauer; Wei Wu; Ji-Yeon Shin; Gisele Bonne; Howard J. Worman; Ohad Medalia

    The LMNA gene encodes the A-type lamins that polymerize into ~3.5 nm thick filaments, and together with B-type lamins and lamin binding proteins form the nuclear lamina. Mutations in LMNA are associated with a wide variety of pathologies. In this study, we analyzed the nuclear lamina of embryonic fibroblasts from LmnaH222P/H222P mice, which develop cardiomyopathy and muscular dystrophy. Although the

    更新日期:2020-10-27
  • Single-cell RNA-sequencing reveals dysregulation of molecular programs associated with SARS-CoV-2 severity and outcomes in patients with chronic lung disease
    bioRxiv. Cell Biol. Pub Date : 2020-10-20
    Linh T. Bui; Nichelle I. Winters; Mei-I Chung; Chitra Joseph; Austin J. Gutierrez; Arun C. Habermann; Taylor S. Adams; Jonas C. Schupp; Sergio Poli; Lance M. Peter; Chase J. Taylor; Jessica B. Blackburn; Bradley W. Richmond; Andrew G. Nicholson; Doris Rassl; William A. Wallace; Ivan O. Rosas; R. Gisli Jenkins; Naftali Kaminski; Jonathan A. Kropski; Nicholas E. Banovich; the Human Cell Atlas Lung Biological

    Rationale: Patients with chronic lung disease have an increased risk for severe coronavirus disease-19 (COVID-19) and poor outcomes. Objectives: To identify molecular characteristics of diseased lung epithelial and immune cells that may account for worse COVID-19 outcomes in patients with chronic lung diseases. Methods: We analyzed the transcriptomes of 605,904 single cells isolated from healthy (79

    更新日期:2020-10-27
  • Pharmacological CDK4/6 inhibition unravels a p53-induced secretory phenotype in senescent cells
    bioRxiv. Cell Biol. Pub Date : 2020-10-20
    Boshi Wang; Simone Brandenburg; Alejandra Hernandez-Segura; Thijmen van Vliet; Elisabeth M. Jongbloed; Saskia M Wilting; Naoko Ohtani; Agnes Jager; Marco Demaria

    Cellular senescence is a state of stable growth arrest that acts as a tumor suppressive mechanism. Several anti-cancer interventions function partly by inducing malignant cells into senescence. However, because of systemic administration and lack of specificity, anti-cancer treatments are associated with premature senescence of various non-malignant cells. Therapy-induced non-malignant senescent cells

    更新日期:2020-10-27
  • SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 are Expressed in the Pancreas but are Not Enriched in Islet Endocrine Cells
    bioRxiv. Cell Biol. Pub Date : 2020-10-20
    Katie C Coate; JeeYeon Cha; Shristi Shrestha; Wenliang Wang; Luciana Mateus Goncalves; Joana Almaca; Meghan E Kapp; Maria Fasolino; Ashleigh Morgan; Chunhua Dai; Diane C Saunders; Rita Bottino; Radhika Aramandla; Regina Jenkins; Roland Stein; Klaus H Kaestner; Golnaz Vahedi; Marcela Brissova; Alvin C Powers

    Reports of new-onset diabetes and diabetic ketoacidosis in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2, the virus that causes COVID-19, is directly cytotoxic to pancreatic islet beta cells. This would require binding and entry of SARS-CoV-2 into host beta cells via cell surface co-expression of ACE2 and TMPRSS2, the putative receptor and effector protease, respectively. To

    更新日期:2020-10-20
  • Conserved cholesterol-related activities of Dispatched drive Sonic hedgehog shedding from the cell membrane
    bioRxiv. Cell Biol. Pub Date : 2020-10-20
    Kay Grobe; Kristina Ehring; Dominique Manikowski; Jurij Froese; Petra Jakobs; Fabian Gude; Ursula Rescher; Jonas Goretzko

    The Sonic hedgehog (Shh) pathway controls embryonic development and tissue homeostasis after birth. Long-lasting questions about this pathway are how dual-lipidated, firmly plasma membrane-associated Shh ligand is released from producing cells to signal to distant target cells, and how the resistance-nodulation-division transporter Dispatched (Disp) regulates this process. Here we show that Disp inactivation

    更新日期:2020-10-20
  • Phospholipid flippases and Sfk1 are essential for the retention of ergosterol in the plasma membrane
    bioRxiv. Cell Biol. Pub Date : 2020-10-20
    Takuma Kishimoto; Tetsuo Mioka; Eriko Itoh; David E Williams; Raymond J Andersen; Kazuma Tanaka

    Sterols are important lipid components of the plasma membrane (PM) in eukaryotic cells, but it is unknown how the PM retains sterols at a high concentration. Phospholipids are asymmetrically distributed in the PM, and phospholipid flippases play an important role in generating this phospholipid asymmetry. Here, we provide evidence that phospholipid flippases are essential for retaining ergosterol in

    更新日期:2020-10-20
  • Internalization of the host alkaline pH signal in a fungal pathogen
    bioRxiv. Cell Biol. Pub Date : 2020-10-19
    Hannah Elizabeth Brown; J. Andrew Alspaugh; Kaila M Pianalto; Katherine D Mueller; Caroline M Fernandes; Maurizio Del Poeta

    The ability for cells to internalize extracellular cues allows them to adapt to novel and stressful environments. This adaptability is especially important for microbial pathogens that must sense and respond to drastic changes when encountering the human host. Cryptococcus neoformans is an environmental fungus and opportunistic pathogen that naturally lives in slightly acidic reservoirs, but must adapt

    更新日期:2020-10-20
  • Primed smooth muscle cells acting as first responder cells in disease
    bioRxiv. Cell Biol. Pub Date : 2020-10-19
    Matthew D Worssam; Jordi Lambert; Sebnem Oc; Annabel L Taylor; Lina Dobnikar; Joel Chappell; Jennifer L Harman; Nichola L Figg; Alison Finigan; Kirsty Foote; Anna K Uryga; Martin R Bennett; Mikhail spivakov; Helle Jorgensen

    Rationale; Vascular smooth muscle cell (VSMC) dysregulation is a hallmark of vascular disease, including atherosclerosis. In particular, the majority of cells within atherosclerotic lesions are generated from pre-existing VSMCs and a clonal nature has been documented for VSMC-derived cells in multiple disease models. However, the mechanisms underlying the generation of oligoclonal lesions and the phenotype

    更新日期:2020-10-20
  • Cyclase-associated protein 2 (CAP2) controls MRTF-A localization and SRF activity in mouse embryonic fibroblasts
    bioRxiv. Cell Biol. Pub Date : 2020-10-19
    Lara-Jane Kepser; Laura Soto Hinojosa; Chiara Macchi; Massimiliano Ruscica; Elena Marcello; Carsten Culmsee; Robert Grosse; Marco B. Rust

    Recent studies identified cyclase-associated proteins (CAPs) as important regulators of actin dynamics that control assembly and disassembly of actin filaments (F-actin). While these studies significantly advanced our knowledge of their molecular functions, the physiological relevance of CAPs largely remained elusive. Gene targeting in mice implicated CAP2 in heart physiology and skeletal muscle development

    更新日期:2020-10-20
  • Interdomain interactions regulate the localization of a lipid transfer protein at ER-PM contact sites
    bioRxiv. Cell Biol. Pub Date : 2020-10-19
    Bishal Basak; Harini Krishnan; Padinjat Raghu

    During phospholipase C-β (PLC-β) signalling in Drosophila photoreceptors, the phosphatidylinositol transfer protein (PITP) RDGB, is required for lipid transfer at endoplasmic reticulum (ER)-plasma membrane (PM) contact sites (MCS). Depletion of RDGB or its mis-localization away from the ER-PM MCS results in multiple defects in photoreceptor function. Previously, the interaction between the FFAT motif

    更新日期:2020-10-20
  • Dynein-dynactin segregate meiotic chromosomes in C. elegans spermatocytes
    bioRxiv. Cell Biol. Pub Date : 2020-10-19
    Daniel Barbosa; Vanessa Teixeira; Joana Duro; Ana Carvalho; Reto Gassmann

    The dynactin complex is an essential co-factor of the microtubule-based motor dynein. Dynein-dynactin have well-documented roles in spindle assembly and positioning during C. elegans female meiosis and embryonic mitosis, while dynein-dynactin's contribution to male meiosis has not been investigated. Here, we characterize the G33S mutation in DNC-1's N-terminal microtubule binding domain, which corresponds

    更新日期:2020-10-20
  • Filopodia-based contact stimulated collective migration drives tissue morphogenesis
    bioRxiv. Cell Biol. Pub Date : 2020-10-19
    Maik Bischoff; Renate Renkawitz-Pohl; Sven Bogdan

    Cells migrate collectively to form tissues and organs during morphogenesis. Contact inhibition of locomotion (CIL) drives collective migration by inhibiting lamellipodial protrusions at cell-cell contacts and promoting polarization at the leading edge. Here, we report on a CIL-related collective cell behavior of myotubes that lack lamellipodial protrusions, but instead use filopodia to move as a cohesive

    更新日期:2020-10-20
  • PIEZO1-induced cellular retraction controls keratinocyte migration in wound healing
    bioRxiv. Cell Biol. Pub Date : 2020-10-19
    Jesse R Holt; Wei-Zheng Zeng; Elizabeth L Evans; Seung-Hyun Woo; Shang Ma; Hamid Abuwarda; Meaghan Loud; Ardem Patapoutian; Medha M Pathak

    Keratinocytes are the predominant cell type of the epidermis and form an important protective barrier to the external environment. During the healing of wounded skin, keratinocytes migrate from the wound edge to reinstate the epithelial barrier. Mechanical cues are important regulators of cell migration in this process; however, the molecular transducers and biophysical mechanisms of this mechanoregulation

    更新日期:2020-10-20
  • Adult Stem Cell-derived Complete Lung Organoid Models Emulate Lung Disease in COVID-19
    bioRxiv. Cell Biol. Pub Date : 2020-10-19
    Courtney Tindle; MacKenzie Fuller; Ayden Fonseca; Sahar Taheri; Stella-Rita Ibeawuchi; Nathan Beutler; Amanraj Claire; Vanessa Castillo; Moises Hernandez; Hana Russo; Jason Duran; Laura E. Crotty Alexander; Ann Tipps; Grace Lin; Patricia A. Thistlethwaite; Ranajoy Chattopadhyay; Thomas F. Rogers; Debashis Sahoo; Pradipta Ghosh; Soumita Das

    SARS-CoV-2, the virus responsible for COVID-19, causes widespread damage in the lungs in the setting of an overzealous immune response whose origin remains unclear. We present a scalable, propagable, personalized, cost-effective adult stem cell-derived human lung organoid model that is complete with both proximal and distal airway epithelia. Monolayers derived from adult lung organoids (ALOs), primary

    更新日期:2020-10-19
  • Cysteine residues in the C-terminal tail of connexin32 regulate its trafficking
    bioRxiv. Cell Biol. Pub Date : 2020-10-18
    Anuttoma Ray

    Gap junctions (GJ)s are formed by the assembly of constituent transmembrane proteins called connexins (Cxs). Aberrations in this assembly of Cxs are observed in several genetic diseases as well as in cancers. Hence it becomes imperative to understand the molecular mechanisms underlying such assembly defect. The polarized cells in the epithelia express Connexin32 (Cx32). The carboxyl-terminal tail (CT)

    更新日期:2020-10-19
  • Practical Fluorescence Reconstruction Microscopy for Large Samples and Low-Magnification Imaging
    bioRxiv. Cell Biol. Pub Date : 2020-10-18
    Julienne LaChance; Daniel J. Cohen

    Fluorescence reconstruction microscopy (FRM) describes a class of techniques where transmitted light images are passed into a convolutional neural network which then outputs predicted epifluorescence images. This approach enables many benefits including reduced phototoxicity, freeing up of fluorescence channels, simplified sample preparation, and the ability to re-process legacy data for new insights

    更新日期:2020-10-19
  • ALS-linked mutations impair UBQLN2 stress-induced biomolecular condensate assembly in cells
    bioRxiv. Cell Biol. Pub Date : 2020-10-18
    Julia F Riley; Heidi Hehnly; Carlos A Castañeda

    Mutations in Ubiquilin-2 (UBQLN2), a ubiquitin-binding shuttle protein involved in several protein quality control processes, can lead to amyotrophic lateral sclerosis (ALS). We previously found that wild-type UBQLN2 forms dynamic, membraneless biomolecular condensates upon cellular stress, and undergoes liquid-liquid phase separation in vitro. However, the impact of ALS-linked mutations on UBQLN2

    更新日期:2020-10-19
  • Mitochondrial profiling reveals dynamic, sex- and age-specific mitochondrial phenotypes in human immune cell subtypes
    bioRxiv. Cell Biol. Pub Date : 2020-10-16
    Shannon Rausser; Caroline Trumpff; Marlon A McGill; Alex Junker; Wei Wang; Siu-Hong Ho; Anika Mitchell; Kalpita R Karan; Catherine Monk; Suzanne C Segerstrom; Rebecca G Reed; Martin Picard

    How mitochondria functionally differ between immune cell subtypes, between the sexes, across ages, and whether they dynamically change over time has not been characterized. Here we deploy a high-throughput mitochondrial phenotyping platform to define cell-type specific mitochondrial features in circulating immune cell subtypes. In women and men spanning four decades of life, we find that mitochondrial

    更新日期:2020-10-17
  • Aberrant Epithelial Differentiation Contributes to Pathogenesis in a Murine Model of Congenital Tufting Enteropathy
    bioRxiv. Cell Biol. Pub Date : 2020-10-16
    Barun Das; Kevin Okamoto; John Rabalais; Jocelyn Young; Kim E. Barrett; Mamata Sivagnanam

    Background & Aims: Congenital Tufting Enteropathy (CTE) is an intractable diarrheal disease of infancy caused by mutation of Epithelial Cell Adhesion Molecule (EpCAM). The cellular and molecular basis of CTE pathology has been elusive. We hypothesized that the loss of EpCAM in CTE results in altered lineage differentiation and defects in absorptive enterocytes thereby contributing to CTE pathogenesis

    更新日期:2020-10-17
  • Cytoplasmic innate immune sensing by the caspase-4 non-canonical inflammasome promotes cellular senescence.
    bioRxiv. Cell Biol. Pub Date : 2020-10-16
    Irene Fernandez Duran; Nuria Tarrats; Jodie Birch; Priya Hari; Fraser R. Millar; Morwenna Muir; Andrea Quintanilla; Valerie G. Brunton; Joao F. Passos; Juan Carlos Acosta

    Cytoplasmic recognition of microbially derived lipopolysaccharides (LPS) in human cells is elicited by the inflammatory cysteine aspartic proteases caspase-4 and caspase-5, which activate non-canonical inflammasomes inducing a form of inflammatory programmed cell death termed pyroptosis. Here we show that LPS mediated activation of the non-canonical inflammasome also induces cellular senescence and

    更新日期:2020-10-17
  • The chromatin-binding domain of Ki-67 together with p53 protects human chromosomes from mitotic damage
    bioRxiv. Cell Biol. Pub Date : 2020-10-16
    Osama Garwain; Xiaoming Sun; Divya Ramalingam Iyer; Rui Li; Lihua Julie Zhu; Paul D. Kaufman

    Vertebrate mammals express a protein called Ki-67 which is most widely known as a clinically useful marker of highly proliferative cells. Previous studies of human cells indicated that acute depletion of Ki-67 can elicit a delay at the G1/S boundary of the cell cycle, dependent on induction of the checkpoint protein p21. Consistent with those observations, we show here that acute Ki-67 depletion causes

    更新日期:2020-10-17
  • Non-rodent mammalian zygotes assemble dual spindles despite the presence of paternal centrosomes
    bioRxiv. Cell Biol. Pub Date : 2020-10-16
    Isabell Schneider; Marta de Ruijter-Villani; M. Julius Hossain; Tom A. E. Stout; Jan Ellenberg

    The first mitosis of the mammalian embryo must partition the parental genomes contained in two pronuclei. In rodent zygotes, sperm centrosomes are degraded and, instead, acentriolar microtubule organizing centers and microtubule self-organization guide the assembly of two separate spindles around the genomes. In non-rodent mammals, including human or bovine, centrosomes are inherited from the sperm

    更新日期:2020-10-17
  • De Novo Lipid Labeling for Comprehensive Analysis of Subcellular Distribution and Trafficking in Live Cells
    bioRxiv. Cell Biol. Pub Date : 2020-10-16
    Jun Zhang; Jia Nie; Haoran Sun; John-Paul Andersen; Yuguang Shi

    Lipids exert dynamic biological functions which are determined both by their fatty acyl compositions and precise spatiotemporal distributions inside the cell. There are more than 1000 lipid species in a typical mammalian cell. However, it remains a daunting task to investigate any of these features in live cells for each of the more than 1000 lipid species. Here we resolved this issue by developing

    更新日期:2020-10-17
  • Bromodomain Inhibition Blocks Inflammation-Induced Cardiac Dysfunction and SARS-CoV2 Infection in Pre-Clinical Models
    bioRxiv. Cell Biol. Pub Date : 2020-10-16
    Richard J Mills; Sean J Humphrey; Partrick RJ Fortuna; Gregory A Quaife-Ryan; Mary Lor; Rajeev Ruraraju; Daniel J Rawle; Thuy Le; Wei Zhao; Leo Lee; Charley Mackenzie-Kludas; Neda R Mehdiabadi; Lynn Devilee; Holly K Voges; Liam T Reynolds; Sophie Krumeich; Ellen Mathieson; Dad Abu-Bonsrah; Kathy Karavendzas; Brendan Griffen; Drew M Titmarsh; David A Elliott; James H McMahon; Andreas Suhrbier; Kanta

    Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined, but could be through direct cardiac infection and/or cytokine-storm induced dysfunction. To identify mechanisms and discover cardio-protective therapeutics, we use a state-of-the-art pipeline combining human cardiac organoids with high throughput phosphoproteomics and single nuclei

    更新日期:2020-10-17
  • Anatomical identification of the neuroendocrine system in the Nothobranchius furzeri brain
    bioRxiv. Cell Biol. Pub Date : 2020-10-16
    Eunjeong Do; Yumi Kim

    The hypophysis functions as a central gland of the neuroendocrine system for regulating fundamental body physiology. Upon aging, several hormones produced by the endocrine system are dramatically altered. Recently, Nothobranchius furzeri (the turquoise killifish) has become a popular model for aging studies because of its short lifespan and highly conserved aging phenotypes. However, the anatomical

    更新日期:2020-10-17
  • POLArIS, a versatile probe for molecular orientation, revealed actin filaments associated with microtubule asters in early embryos
    bioRxiv. Cell Biol. Pub Date : 2020-10-16
    Ayana Sugizaki; Keisuke Sato; Kazuyoshi Chiba; Kenta Saito; Masahiko Kawagishi; Yuri Tomabechi; Shalin B. Mehta; Hirokazu Ishii; Naoki Sakai; Mikako Shirouzu; Tomomi Tani; Sumio Terada

    Biomolecular assemblies govern the physiology of cells. Their function often depends on the changes in molecular arrangements of constituents, both in the positions and orientations. While recent advancements of fluorescence microscopy including super-resolution microscopy have enabled us to determine the positions of fluorophores with unprecedented accuracy, monitoring orientation of fluorescently

    更新日期:2020-10-17
  • The Adaptor Protein Complex 1 limits E-cadherin endocytosis during epithelial morphogenesis
    bioRxiv. Cell Biol. Pub Date : 2020-10-16
    Miguel Ramírez Moreno; Katy Boswell; Natalia A Bulgakova

    Intracellular trafficking regulates the distribution of transmembrane proteins including the key determinants of epithelial polarity and adhesion. The Adaptor Protein 1 (AP-1) complex is the key regulator of vesicle sorting, which binds a large number of specific cargos. We examined roles of the AP-1 complex in epithelial morphogenesis, using the Drosophila wing as a paradigm. We found that AP-1 knockdown

    更新日期:2020-10-17
  • Coronin-1 is necessary for enteric pathogen-induced transcytosis across human ileal enteroid monolayers expressing M cells
    bioRxiv. Cell Biol. Pub Date : 2020-10-16
    Janet F Staab; Michele Doucet; Rachel Latanich; Sun Lee; Mary K Estes; James B Kaper; Nicholas Zachos

    In the intestine, luminal sampling by microfold (M) cells is crucial for inducing protective mucosal immune responses but can also serve as an entry pathway for pathogens, including bacteria and viruses. Enteric pathogens can influence intestinal M cell function; however, the molecular mechanisms involved in the regulation of uptake and transcytosis of gut cargo by human M cells remain to be determined

    更新日期:2020-10-17
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