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| Open AccessSynaptotagmin-13 orchestrates pancreatic endocrine cell egression and islet morphogenesis
How pancreatic islets of Langerhans are built during development is incompletely understood. Here the authors find that Synaptotagmin-13 mediates remodeling of cell-matrix adhesion to regulate endocrine cell egression and islet morphogenesis.
- Mostafa Bakhti
- , Aimée Bastidas-Ponce
- & Heiko Lickert
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Article
| Open AccessRep15 interacts with several Rab GTPases and has a distinct fold for a Rab effector
Rep15 is an effector that interacts with the GTPase Rab15. Here, the authors show that Rep15 also interacts with Rab3 paralogs and Rab34, present crystal structures of Rep15:Rab complexes and find that Rep15 depletion in glioblastoma cells decreases proliferation and mobility.
- Amrita Rai
- , Anurag K. Singh
- & Roger S. Goody
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Article
| Open AccessNeuropilin 1 and its inhibitory ligand mini-tryptophanyl-tRNA synthetase inversely regulate VE-cadherin turnover and vascular permeability
Functional vascular tree formation is a key step in many contexts, such as cancer, and Neuropilin1 (NRP1) has been associated with adhesion receptor endocytic turnover. Here, authors show NRP1 and its mini-WARS ligand play a role in reducing endothelial permeability.
- Noemi Gioelli
- , Lisa J. Neilson
- & Guido Serini
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Article
| Open AccessStomatin modulates adipogenesis through the ERK pathway and regulates fatty acid uptake and lipid droplet growth
Stomatin is a component of lipid rafts. Here, Wu et al. show that stomatin modulates the differentiation and functions of adipocytes by regulating adipogenesis signaling and fatty acid influx such that with excessive calorie intake, increased stomatin induces adiposity.
- Shao-Chin Wu
- , Yuan-Ming Lo
- & Chi-Hung Lin
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Article
| Open AccessHRS phosphorylation drives immunosuppressive exosome secretion and restricts CD8+ T-cell infiltration into tumors
Lack of CD8+ T-cell infiltration into solid tumors is associated with poor responsiveness to immune checkpoint therapy (ICT). Here, the authors show that blocking the phosphorylation of HRS to reduce the induction of immunosuppressive exosomes promotes CD8+ T-cell infiltration into tumors and enhances the efficacy of ICT in mouse melanoma models.
- Lei Guan
- , Bin Wu
- & Wei Guo
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Article
| Open AccessCiliary transition zone proteins coordinate ciliary protein composition and ectosome shedding
Cilia project from cells to serve sensory functions, and ciliary disruption can result in multiple disorders known as ciliopathies. Here the authors show that the ciliopathy gene TCTN1 functions to regulate the ciliary transition zone and ectosome formation.
- Liang Wang
- , Xin Wen
- & Muqing Cao
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Article
| Open AccessEndosomal LC3C-pathway selectively targets plasma membrane cargo for autophagic degradation
Autophagy can selectively target cargo for degradation. Here the authors map the proximal interactome of ATG8-paralogs LC3B and LC3C uncovering an LC3C-Endocytic-Associated-Pathway that selectively recruits internalized plasma membrane cargo, Met and transferrin receptors, to nascent autophagosomes.
- Paula P. Coelho
- , Geoffrey G. Hesketh
- & Morag Park
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Article
| Open AccessStructural basis for mitoguardin-2 mediated lipid transport at ER-mitochondrial membrane contact sites
The ER-mitochondria contact sites are crucial for exchanging phospholipids. Here, Kim et al. present crystal structures of mitoguardin-2 (MIGA2) which reveal that MIGA2 directly binds phospholipids and transfers them between the ER and mitochondria.
- Hyunwoo Kim
- , Seowhang Lee
- & Changwook Lee
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Article
| Open AccessA degradative to secretory autophagy switch mediates mitochondria clearance in the absence of the mATG8-conjugation machinery
The mechanisms underlying mitochondrial quality control are not fully understood. Here the authors identify a switch from degradative to secretory autophagy in the absence of the mATG8-conjugation system, termed Autophagic Secretion of Mitochondria.
- Hayden Weng Siong Tan
- , Guang Lu
- & Han-Ming Shen
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Article
| Open AccessMolecular mechanics underlying flat-to-round membrane budding in live secretory cells
Shin et al. report the molecular mechanics of membrane budding: actin and dynamin pull membrane inward to form a Λ-shape profile; dynamin helices convert Λ- to Ω-shape by constricting Λ’s base, and then constrict Ω-profile’s pore to form a vesicle.
- Wonchul Shin
- , Ben Zucker
- & Ling-Gang Wu
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Article
| Open AccessBranched actin networks are organized for asymmetric force production during clathrin-mediated endocytosis in mammalian cells
Drubin et al. use three different advanced imaging approaches to show that actin assembles preferentially at stalled clathrin-mediated endocytosis sites, where the actin pulls vesicles into the cell asymmetrically, as a bottle opener pulls off a cap.
- Meiyan Jin
- , Cyna Shirazinejad
- & David G. Drubin
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Article
| Open AccessT-cell trans-synaptic vesicles are distinct and carry greater effector content than constitutive extracellular vesicles
T cells communicate with antigen-presenting cells (APC) via the signaling crosstalk at the immunological synapse (IS). Here the authors use bead-supported lipid bilayers as synthetic APCs to find that trans-synaptic vesicles produced by T cells in the IS carry specialized cargos distinct from constitutive extracellular vesicles to serve as intercellular messengers.
- Pablo F. Céspedes
- , Ashwin Jainarayanan
- & Michael L. Dustin
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Article
| Open AccessAsgard archaea shed light on the evolutionary origins of the eukaryotic ubiquitin-ESCRT machinery
The ESCRT pathway is crucial for membrane remodelling in eukaryotes. Here, Hatano et al. explore the phylogeny, structure, and biochemistry of homologues of the ESCRT machinery and the associated ubiquitylation system in Asgard archaea, the closest living relatives of eukaryotes.
- Tomoyuki Hatano
- , Saravanan Palani
- & Mohan Balasubramanian
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Article
| Open AccessEfferocytosis requires periphagosomal Ca2+-signaling and TRPM7-mediated electrical activity
Efficient removal of apoptotic cells by phagocytosis underlies tissue development, wound repair, host defense and organ homeostasis. Here, authors identify TRPM7 as a regulator of cargo acidification and Ca2+ signaling during apoptotic cell clearance.
- Michael S. Schappe
- , Marta E. Stremska
- & Bimal N. Desai
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Article
| Open AccessCa2+-mediated higher-order assembly of heterodimers in amino acid transport system b0,+ biogenesis and cystinuria
Cystinuria is caused by mutations in heterodimeric amino acid transporter known as system b0,+. Here, authors discover that Ca2+ stabilizes the interface between two system b0,+ regulatory subunits rBAT, leading to super-dimerization of the b0,+AT–rBAT heterodimer, facilitating system b0,+ maturation.
- Yongchan Lee
- , Pattama Wiriyasermkul
- & Shushi Nagamori
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Article
| Open AccessSmall extracellular vesicle-mediated miR-320e transmission promotes osteogenesis in OPLL by targeting TAK1
The pathological mechanisms that lead to Ossification of the posterior longitudinal ligament (OPLL) are unclear. Here, the authors show that OPLL ligament cells produce small extracellular vesicles that induce ossification via miR-320e/TAK1 signaling in mice and human posterior longitudinal ligament cells.
- Chen Xu
- , Zicheng Zhang
- & Wen Yuan
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Article
| Open AccessCul3-KLHL20 E3 ubiquitin ligase plays a key role in the arms race between HIV-1 Nef and host SERINC5 restriction
SERINC5 is a host-restriction factor preventing HIV progeny entry, which is counteracted by interactions with HIV Nef. Here, Li et al. show that E3 ubiquitin ligase Cullin 3 polyubiquitinates SERINC5 at Lys 130 via K48- and K33-linked ubiquitin chains and provide evidence that this modification is not only required for its membrane localization and anti-viral activity but also relevant for Nef counteractive activity.
- Sunan Li
- , Rongrong Li
- & Yong-Hui Zheng
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Article
| Open AccessSnf7 spirals sense and alter membrane curvature
Snf7 is the major component of the ESCRTIII membrane deformation system. Here, the authors used high-speed AFM to study Snf7 on nano-patterned and soft supports and show that loaded Snf7 spiral springs are curvature sensitive and deform membranes.
- Nebojsa Jukic
- , Alma P. Perrino
- & Simon Scheuring
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Article
| Open AccessLocal and substrate-specific S-palmitoylation determines subcellular localization of Gαo
How palmitoylated proteins specifically localize is not fully understood. Here, authors created the SwissKASH assay to visualize S-palmitoylation in cells and uncovered a striking substrate selectivity of acyltransferases at the core of this process.
- Gonzalo P. Solis
- , Arghavan Kazemzadeh
- & Vladimir L. Katanaev
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Article
| Open AccessPhagosomal signalling of the C-type lectin receptor Dectin-1 is terminated by intramembrane proteolysis
Dectin-1 is a critical component of the innate sensing repertoire which is involved in pattern based recognition of fungal pathogens. Here the authors show that intramembrane proteolysis is involved in the regulation of the antifungal host response by termination of the phagosomal signalling of Dectin-1.
- Torben Mentrup
- , Anna Yamina Stumpff-Niggemann
- & Bernd Schröder
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Article
| Open AccessThe PripA-TbcrA complex-centered Rab GAP cascade facilitates macropinosome maturation in Dictyostelium
Macropinocytosis has emerged as an evolutionarily conserved mechanism for bulk uptake of extracellular fluid. Here they show how a Rab GAP cascade centered on the PripA-TbcrA complex facilitates Rab conversion and macropinosome maturation.
- Hui Tu
- , Zhimeng Wang
- & Huaqing Cai
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Article
| Open AccessImaging vesicle formation dynamics supports the flexible model of clathrin-mediated endocytosis
Despite decades of research, the dynamics of clathrin-coated vesicle formation is ambiguous. Here, authors use STAR microscopy to quantify the nanoscale dynamics of vesicle formation, supporting the flexible model of clathrin-mediated endocytosis.
- Tomasz J. Nawara
- , Yancey D. Williams II
- & Alexa L. Mattheyses
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Article
| Open AccessUBR4/POE facilitates secretory trafficking to maintain circadian clock synchrony
Although ubiquitin ligases are known to control clock protein degradation, their other roles in clock neurons are unclear. Here the authors report that UBR4 promotes export of neuropeptides from the Golgi for axonal trafficking, which is important for circadian clock synchrony in mice and flies.
- Sara Hegazi
- , Arthur H. Cheng
- & Hai-Ying Mary Cheng
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Article
| Open AccessRUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin
Organellar transport is carefully regulated, and endolysosome localized ARL8 is important for kinesin recruitment and anterograde movement. Here, the authors show that RUFY3 and RUFY4 promote retrograde transport of endolysosomes by mediating interaction of ARL8 with dynein-dynactin.
- Tal Keren-Kaplan
- , Amra Sarić
- & Juan S. Bonifacino
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Article
| Open AccessRUFY3 links Arl8b and JIP4-Dynein complex to regulate lysosome size and positioning
Lysosomes move along microtubule tracks, and Arl8b is known to stimulate their anterograde transport. Here, the authors identified RUFY3 as an Arl8b effector that interacts with dynein-dynactin to drive retrograde transport and perinuclear lysosome positioning.
- Gaurav Kumar
- , Prateek Chawla
- & Amit Tuli
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Article
| Open AccessAP-4-mediated axonal transport controls endocannabinoid production in neurons
Davies et al. identify a putative mechanism underlying the childhood neurological disorder AP-4 deficiency syndrome. In the absence of AP-4, an enzyme that makes 2-AG is not transported to the axon, leading to axonal growth defects, which can be rescued by inhibition of 2-AG breakdown.
- Alexandra K. Davies
- , Julian E. Alecu
- & Georg H. H. Borner
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Article
| Open AccessDual clathrin and integrin signaling systems regulate growth factor receptor activation
The integration and organization of growth factor signaling, adhesion, and endocytosis is poorly understood. Here the authors use light and electron microscopy to shed light on the role of flat clathrin lattices and cell adhesion in growth factor signaling.
- Marco A. Alfonzo-Méndez
- , Kem A. Sochacki
- & Justin W. Taraska
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Article
| Open AccessSchwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice
The mechanism of CGRP-evoked peripheral pain is unclear. Here, the authors show that the CGRP-mediated neuronal/Schwann cell pathway mediates allodynia associated with neurogenic inflammation, contributing to the algesic action of CGRP in mice.
- Francesco De Logu
- , Romina Nassini
- & Pierangelo Geppetti
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Article
| Open AccessLima1 mediates the pluripotency control of membrane dynamics and cellular metabolism
How pluripotency transcription factors regulate the cellular architecture and energetics has remained largely unknown. Here the authors identify Lima1 as a key effector that mediates the pluripotency control of membrane dynamics and cellular metabolism.
- Binyamin Duethorn
- , Fabian Groll
- & Ivan Bedzhov
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Article
| Open AccessLung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice
Excess macrophage elastase MMP-12 is a major driver of chronic obstructive pulmonary disease. Here the authors show that the endolysosomal ion channel TRPML3 is a regulator of the cellular reuptake of MMP-12, thus neutralizing harmful MMP-12 in the lung.
- Barbara Spix
- , Elisabeth S. Butz
- & Christian Grimm
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Article
| Open AccessEndosomal trafficking defects alter neural progenitor proliferation and cause microcephaly
Mutations in the human WDR81 gene result in severe microcephaly. Carpentieri et al. show that mutation of WDR81, a gene coding for an endosomal regulator, alters intracellular processing of the EGF receptor, leading to reduced proliferation rates of neuronal progenitors and to microcephaly.
- Jacopo A. Carpentieri
- , Amandine Di Cicco
- & Alexandre D. Baffet
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Article
| Open AccessSpatial control of avidity regulates initiation and progression of selective autophagy
The molecular principles governing the initiation of autophagosome formation are not clearly understood. Here we show that the vacuolar protein Vac8 coordinates this process by promoting an avidity-driven assembly of several autophagy factors.
- David M. Hollenstein
- , Mariya Licheva
- & Claudine Kraft
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Article
| Open AccessExtracellular matrix remodeling through endocytosis and resurfacing of Tenascin-R
Synapses are surrounded by an extracellular matrix (ECM) of extremely long-lived proteins that is thought to only be remodeled by proteolysis and de novo synthesis. Here, the authors show an alternative molecular recycling mechanism that occurs for the key ECM protein Tenascin-R.
- Tal M. Dankovich
- , Rahul Kaushik
- & Silvio O. Rizzoli
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Article
| Open AccessWFS1 functions in ER export of vesicular cargo proteins in pancreatic β-cells
The role of cargo receptors in proinsulin export from the ER is unclear. Here, the authors identify the WFS1 protein, which is mutated in Wolfram syndrome and associated with diabetes, as an ER to Golgi cargo receptor required for normal insulin processing and secretion.
- Linlin Wang
- , Hongyang Liu
- & Zonghong Li
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Article
| Open AccessNuclear-capture of endosomes depletes nuclear G-actin to promote SRF/MRTF activation and cancer cell invasion
Effective delivery of signals from the cell surface to the nucleus is a key to activate gene transcription. Here, the authors show how endosomes containing EphA2 are transported and captured at the nuclear surface, triggering depletion of G-actin from the nucleus and activating MRTF signalling.
- Sergi Marco
- , Matthew Neilson
- & Jim C. Norman
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Article
| Open AccessThe autophagy protein ATG9A enables lipid mobilization from lipid droplets
ATG9A is transmembrane autophagic machinery protein that delivers phospholipids to expanding autophagosomes. Mailler et al. show that ATG9A is required to mobilize lipids from lipid droplets for autophagosome expansion as well as mitochondrial fatty acid import and β-oxidation.
- Elodie Mailler
- , Carlos M. Guardia
- & Juan S. Bonifacino
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Article
| Open AccessmTOR-mediated phosphorylation of VAMP8 and SCFD1 regulates autophagosome maturation
Autophagy relies on coordinated fusion of organelle membranes, although the interplay between the regulatory machinery is not well studied. Here, the authors show that SNARE complex formation is inhibited by mTORC1 phosphorylation of VAMP8, which prevents autophagosome-lysosome fusion.
- Hong Huang
- , Qinqin Ouyang
- & Rong Liu
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Article
| Open AccessToxin secretion and trafficking by Mycobacterium tuberculosis
The tuberculosis necrotizing toxin (TNT) is the major cytotoxicity factor of M. tuberculosis (Mtb). Mtb possesses five type VII secretion systems (ESX). Pajuelo et al. show that the ESX-4 system is required for TNT secretion and that ESX-2 and ESX-4 systems work in concert with ESX-1 to permeabilize the phagosomal membrane and enable trafficking of TNT into the cytoplasm of macrophages infected with Mtb.
- David Pajuelo
- , Uday Tak
- & Michael Niederweis
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Article
| Open AccessFree energies of membrane stalk formation from a lipidomics perspective
Fusion of cellular membranes begins with the formation of a stalk. Here, the authors develop a computationally efficient method for coarse-grained simulations of stalk formation and apply this approach to comprehensively analyse how stalk formation is influenced by the membrane lipid composition.
- Chetan S. Poojari
- , Katharina C. Scherer
- & Jochen S. Hub
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Article
| Open AccessThe phosphoinositide coincidence detector Phafin2 promotes macropinocytosis by coordinating actin organisation at forming macropinosomes
Macropinocytosis permits the cellular uptake of fluids and nutrients via macropinosomes. Here, the authors show that Phafin2 is required for the formation of macropinosomes and permits their transit through dense actin networks.
- Kay Oliver Schink
- , Kia Wee Tan
- & Harald Stenmark
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Article
| Open AccessLysine acetylation regulates the interaction between proteins and membranes
Lysine acetylation regulates the function of soluble proteins in vivo, yet it remains largely unexplored whether lysine acetylation regulates the function of membrane proteins. Here, the authors map lysine acetylation predominantly in membrane-interaction regions in peripheral membrane proteins and show with three candidate proteins how lysine acetylation is a regulator of membrane protein function.
- Alan K. Okada
- , Kazuki Teranishi
- & Ralf Langen
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Article
| Open AccessCoordination of fungal biofilm development by extracellular vesicle cargo
The fungal pathogen Candida albicans can release extracellular vesicles that promote biofilm formation and antifungal resistance. Here, Zarnowski et al. define functions for numerous vesicle cargo proteins in biofilm matrix assembly and drug resistance, as well as in fungal cell adhesion and dissemination.
- Robert Zarnowski
- , Andrea Noll
- & David R. Andes
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Article
| Open AccessCongenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5
Mutations in genes critical for proper intra-Golgi transport can cause human syndromes due to defects in glycosylation of proteins. Here, the authors identify a human variant of Syntaxin-5 that causes fatal multisystem disease and mislocalization of glycosyltransferases due to altered Golgi transport.
- Peter T. A. Linders
- , Eveline C. F. Gerretsen
- & Geert van den Bogaart
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Article
| Open AccessAn active tethering mechanism controls the fate of vesicles
Molecular tethers physically bridge transport vesicles to their target membranes as a prerequisite step for fusion. Here the authors control vesicle tethering using optogenetic approaches to study the interplay between vesicle tethering and fusion.
- Seong J. An
- , Felix Rivera-Molina
- & Derek Toomre
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Article
| Open AccessTRAPPC4 regulates the intracellular trafficking of PD-L1 and antitumor immunity
Transport protein particle (TRAPP) is a multimeric protein complex regulating membrane trafficking pathways. Here the authors show that TRAPPC4, a core subunit of TRAPP complex, is required for RAB11-mediated recycling of PD-L1, affecting T-cell-mediated anti-tumor immune responses.
- Yimeng Ren
- , Yun Qian
- & Jing-Yuan Fang
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Article
| Open AccessCryoEM structure of the super-constricted two-start dynamin 1 filament
Dynamin mediates the fission of vesicles during endocytosis. Here, the authors report the cryoEM structure of a super-constricted two-start dynamin 1 filament- one of the two known helical forms of dynamin, with insights into the molecular mechanisms of dynamin-mediated membrane scission.
- Jiwei Liu
- , Frances Joan D. Alvarez
- & Peijun Zhang
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Article
| Open AccessORP1L mediated PI(4)P signaling at ER-lysosome-mitochondrion three-way contact contributes to mitochondrial division
Membrane contact sites between organelles have specialized functions that are only beginning to be understood. Here, the authors show that ORP1L mediates lysosome recruitment and PI(4)P signaling at endoplasmic reticulum-lysosome-mitochondria three-way contact sites involved in mitochondrial division.
- Maxime Boutry
- & Peter K. Kim
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Article
| Open AccessSequences in the cytoplasmic tail of SARS-CoV-2 Spike facilitate expression at the cell surface and syncytia formation
The Spike protein of SARS-CoV-2 has a C-terminal cytoplasmic tail. Here the authors show that this tail binds trafficking machinery via sequences that appear optimised to ensure that Spike accumulates at the site of viral budding in the Golgi but that some can also traffic to the cell surface to induce syncytia formation.
- Jérôme Cattin-Ortolá
- , Lawrence G. Welch
- & Sean Munro
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Article
| Open AccessDynamic tracking and identification of tissue-specific secretory proteins in the circulation of live mice
The in vivo identification of proteins secreted from a specific cell type or tissue remains challenging. Here, the authors develop a proximity labeling-based method to selectively label secreted proteins and combine it with proteomics to identify liver secretory proteins in mouse plasma.
- Kwang-eun Kim
- , Isaac Park
- & Jae Myoung Suh