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| Open AccessUbiquitination-mediated Golgi-to-endosome sorting determines the toxin-antidote duality of fission yeast wtf meiotic drivers
Meiotic drivers of the wtf family kill progeny lacking the driver by producing a toxin and an antidote. Here, authors reveal that ubiquitination-mediated sorting of the antidote prevents it from becoming toxic and enables it to neutralize the toxin.
- Jin-Xin Zheng
- , Tong-Yang Du
- & Li-Lin Du
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Article
| Open AccessThe TNFR Wengen regulates the FGF pathway by an unconventional mechanism
Mechanistic studies of receptor action have aided our understanding of developmental processes and facilitated drug development. Here they show that the TNFR-Wengen acts by forming a complex with the FGFR-Breathless, regulating its activity during cell differentiation in the developing respiratory system of Drosophila.
- Annalisa Letizia
- , Maria Lluisa Espinàs
- & Marta Llimargas
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Article
| Open AccessDeterministic early endosomal maturations emerge from a stochastic trigger-and-convert mechanism
Newly formed endosomes mature into early endosomes by shedding one protein and acquiring another. Here, the authors describe a trigger-and-convert mechanism driven by endosomal collisions and fusions that govern timeliness in ensemble maturations.
- Harrison M. York
- , Kunaal Joshi
- & Senthil Arumugam
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Article
| Open AccessRUFY3 regulates endolysosomes perinuclear positioning, antigen presentation and migration in activated phagocytes
RUFY proteins are known to regulate autophagy, cytoskeletal dynamics, migration and endosomal trafficking. Here, Char et al. show that iRUFY3 plays a role in perinuclear positioning, phagocyte migration and antigen presentation during Salmonella infection.
- Rémy Char
- , Zhuangzhuang Liu
- & Philippe Pierre
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Article
| Open AccessCryo-electron tomography reveals structural insights into the membrane remodeling mode of dynamin-like EHD filaments
Eps15-homology domain containing proteins comprise a family of dynamin-related ATPases. Here, Melo et al. use cryo-electron tomography to determine the membrane-bound EHD4 structure, therefore clarifying the membrane binding and oligomerization mode.
- Arthur A. Melo
- , Thiemo Sprink
- & Oliver Daumke
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Article
| Open AccessMitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA
Mitochondrial quality control mechanisms prevent damage accumulation, including in mitochondrial DNA (mtDNA). Here, Sen et al. show that altered mtDNA elicits local rearrangements in mitochondrial membrane potential and cristae structure, with mtDNA eliminated through VPS35 endosomes.
- Ayesha Sen
- , Sebastian Kallabis
- & David Pla-Martín
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Article
| Open AccessGlutamyl-prolyl-tRNA synthetase 1 coordinates early endosomal anti-inflammatory AKT signaling
The PI3K/AKT signaling pathway is carefully regulated in specific cellular compartments. Lee and colleagues show that the housekeeping gene glutamyl-prolyl-tRNA synthetase 1 coordinates early endosome-specific AKT signaling necessary for inflammation resolution.
- Eun-Young Lee
- , Su-Man Kim
- & Myung Hee Kim
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Article
| Open AccessCross-linking of the endolysosomal system reveals potential flotillin structures and cargo
Protein complexes play a decisive role for lysosomal function. Here, the authors use cross-linking mass spectrometry and integrative modeling to investigate lysosomes and early endosomes; characterizing protein interactions, structures, and the cargo of flotillin-mediated endocytosis.
- Jasjot Singh
- , Hadeer Elhabashy
- & Dominic Winter
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Article
| Open AccessSpatial snapshots of amyloid precursor protein intramembrane processing via early endosome proteomics
Methods to assess organellar content are important. Here, Park et al develop a method for rapid isolation of early/sorting endosomes and demonstrate the application of the approach for analysis of endosomal proteomes and lipidomes, and for analysis of APP processing to Aβ via β and γ-Secretases.
- Hankum Park
- , Frances V. Hundley
- & J. Wade Harper
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Article
| Open AccessResolving subcellular pH with a quantitative fluorescent lifetime biosensor
Measuring sub-cellular pH with high accuracy and spatiotemporal resolution remains challenging. Here, Johnston and co-workers develop a pH biosensor that combines the pH dependant fluorescent lifetime of mApple with deep learning to accurately determine sub-cellular pH in individual vesicles.
- Joshua J. Rennick
- , Cameron J. Nowell
- & Angus P. R. Johnston
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Article
| Open AccessLocation bias contributes to functionally selective responses of biased CXCR3 agonists
Subcellular signaling is critical to generating cellular responses that modulate inflammatory pathways at the chemokine receptor CXCR3. Eiger et al. determine that agonist-biased CXCR3 signaling at endosomes differs from that at the plasma membrane, proposing location bias as an important phenomenon in signal transduction.
- Dylan Scott Eiger
- , Noelia Boldizsar
- & Sudarshan Rajagopal
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Article
| Open AccessFERARI and cargo adaptors coordinate cargo flow through sorting endosomes
It is estimated that about 80% of endocytosed material is recycled back to the plasma membrane. Here, the authors show that kiss-and-run of Rab5 early endocytic and Rab11 recycling vesicles on sorting endosomes allow cargo flow, providing more robustness and fidelity to the sorting process.
- Jachen A. Solinger
- , Harun-Or Rashid
- & Anne Spang
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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 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 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 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 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 AccessPDZD-8 and TEX-2 regulate endosomal PI(4,5)P2 homeostasis via lipid transport to promote embryogenesis in C. elegans
Cellular membranes have distinct lipid compositions despite intermixing, and it is unclear why plasma membrane lipids do not accumulate on endosomes. Here, the authors use the C. elegans embryo to identify lipid transfer proteins and phosphatases that are critical for endosomal lipid homeostasis.
- Darshini Jeyasimman
- , Bilge Ercan
- & Yasunori Saheki
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Article
| Open AccessSNX19 restricts endolysosome motility through contacts with the endoplasmic reticulum
Endoplasmic reticulum (ER)-interorganelle membrane contact sites have emerged as key regulators of organelle dynamics. Here, the authors report that the ER-resident protein SNX19 mediates ER-endolysosome membrane contacts to maintain the perinuclear distribution of endolysosomes and restrict their motility.
- Amra Saric
- , Spencer A. Freeman
- & Juan S. Bonifacino
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Article
| Open AccessINPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer
The PI(3,4)P2 4-phosphatase, INPP4B, functions as a tumour suppressor in triple negative breast cancer. Here, the authors show that INPP4B enhances proliferation and growth of PIK3CA-mutant ER+ breast cancers by promoting PI3Kα-dependent late endosome formation and trafficking that leads to the activation of Wnt/β-catenin signalling.
- Samuel J. Rodgers
- , Lisa M. Ooms
- & Christina A. Mitchell
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Article
| Open AccessStructural basis for VPS34 kinase activation by Rab1 and Rab5 on membranes
The phosphatidylinositol-3-phosphate (PI3P) is generated by the lipid kinase VPS34, in the context of VPS34 complex I on autophagosomes or complex II on endosomes. Biochemical and structural analyses provide insights into the mechanism of both VPS34 complexes recruitment to and activation on membranes by specific Rab GTPases.
- Shirley Tremel
- , Yohei Ohashi
- & Roger L. Williams
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Article
| Open AccessMechanism and evolution of the Zn-fingernail required for interaction of VARP with VPS29
VARP is bound to endosomes and functions as a protein:protein interaction platform. Here, the authors present the NMR structure of the complex between the retromer subunit VPS29 and a VARP Zn-fingernail microdomain that is structurally distinct from Zn-fingers and further show that mutations, which abolish VPS29:VARP binding, inhibit trafficking from endosomes to the cell surface.
- Harriet Crawley-Snowdon
- , Ji-Chun Yang
- & David J. Owen
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Article
| Open AccessProtrudin and PDZD8 contribute to neuronal integrity by promoting lipid extraction required for endosome maturation
Interorganelle membrane contact sites between the endoplasmic reticulum and the endolysosome. Here, the authors show that ER-endolysosome membrane contact sites are promoted by the proteins protrudin and PDZD8 and may contribute to lipid extraction at these contact sites.
- Michiko Shirane
- , Mariko Wada
- & Keiichi I. Nakayama
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Article
| Open AccessEpsin-mediated degradation of IP3R1 fuels atherosclerosis
Endothelial cell (EC) dysfunction and inflammation contribute to plaque destabilization in atherosclerosis, increasing the risk of thrombotic events. Here, the authors show that epsin promotes EC inflammation via a mechanism involving IP3R1 degradation, and that deletion of epsin in the endothelium prevents EC dysfunctoin and atherosclerosis in mice.
- Yunzhou Dong
- , Yang Lee
- & Hong Chen
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Article
| Open AccessPDZD8 interacts with Protrudin and Rab7 at ER-late endosome membrane contact sites associated with mitochondria
Membrane contact sites between organelles have been shown to play important biological roles. Here, the authors show that at the ER, PDZD8 associates with Protrudin and also with Rab7 endosomes and recruits mitochondria to form three-way contacts.
- Yael Elbaz-Alon
- , Yuting Guo
- & Jodi Nunnari
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Article
| Open AccessTMEM16K is an interorganelle regulator of endosomal sorting
The endolysosomal pathway plays an important role in regulating protein and lipid sorting and degradation. Here, the authors show that TMEM16K, an endoplasmic reticulum lipid scramblase, forms ER-endosome contact sites where it regulates endosomal sorting.
- Maja Petkovic
- , Juan Oses-Prieto
- & Yuh Nung Jan
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Article
| Open AccessKinesin-1 regulates antigen cross-presentation through the scission of tubulations from early endosomes in dendritic cells
Kinesin-1 is a motor protein transporting cargo along microtubules. Here the authors show that kinesin-1 is required for antigen cross-presentation and coordinates endosome scission from early endosomes to allow sorting internalized cargoes towards the recycling endosomal or lysosomal compartments.
- Meriem Belabed
- , François-Xavier Mauvais
- & Gaël Ménasché
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Article
| Open AccessThe cryo-EM structure of the SNX–BAR Mvp1 tetramer
SNX-BAR proteins are a family of PX and BAR domain-containing proteins with pivotal roles in trafficking processes. Here authors present the cryo-EM structure of the full-length fungal SNX-BAR Mvp1, which is an autoinhibited tetramer and provides critical insight into SNX-BAR function and regulation.
- Dapeng Sun
- , Natalia V. Varlakhanova
- & Marijn G. J. Ford
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Article
| Open AccessQuantitative live cell imaging reveals influenza virus manipulation of Rab11A transport through reduced dynein association
Here, using high spatiotemporal resolution light-sheet and fluorescence microscopy, the authors investigate the role of cytoskeletal components on the intracellular transport of Rab11A and influenza virus (IAV) vRNP), and show a preference for Rab11A movement along microtubules that is not essential for IAV vRNP transport.
- Amar R. Bhagwat
- , Valerie Le Sage
- & Seema S. Lakdawala
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Article
| Open AccessFlotillins promote T cell receptor sorting through a fast Rab5–Rab11 endocytic recycling axis
Internalized receptors are recycled back to the cell surface, but their precise mechanisms are unclear. Here, the authors show that the flotillin membrane proteins may regulate the transfer of internalized T cell receptors into Rab5 and Rab11-positive endosomes to support its rapid recycling.
- Gregory M. I. Redpath
- , Manuela Ecker
- & Jérémie Rossy
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Article
| Open AccessLinkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells
Lipid nanoparticles (LNPs) are potential platforms for RNA-based therapeutics, but the fate of LNP-RNAs upon internalization into the cell is unclear. Here, the authors show that LNP-mRNAs and ionizable lipids escape the endosomes and are re-released via extracellular vesicles which could deliver the functional mRNA to other cells.
- Marco Maugeri
- , Muhammad Nawaz
- & Hadi Valadi
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Article
| Open AccessApoptotic signalling targets the post-endocytic sorting machinery of the death receptor Fas/CD95
Fas is a death receptor that regulates apoptosis in many cell types and is downregulated on the cell surface in many cancers. Here, Sharma et al. show that endosome associated trafficking regulator ENTR1 regulates delivery of Fas to lysosomes, thereby controlling its degradation and signalling.
- Shruti Sharma
- , Antonio Carmona
- & Kai S. Erdmann
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Article
| Open AccessWDFY2 restrains matrix metalloproteinase secretion and cell invasion by controlling VAMP3-dependent recycling
WDFY2 is known as a tumour suppressor but its function is unclear. Here, the authors show that WDFY2 interacts with the v-SNARE VAMP3, leading to a suppression of the metalloprotease MT1-MMP secretion, suggesting that WDFY2 acts a tumour suppressor by suppressing MT1-MMP secretion.
- Marte Sneeggen
- , Nina Marie Pedersen
- & Kay Oliver Schink
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Article
| Open AccessZFYVE21 is a complement-induced Rab5 effector that activates non-canonical NF-κB via phosphoinosotide remodeling of endosomes
Complement activation contributes to vascular inflammation in the contexts of allograft rejection and connective tissue disease. Here Fang et al. identify ZFYVE21 as a novel effector of Rab5 and find it regulates pro-inflammatory NF-κB signaling in endothelial cells in response to complement activation.
- Caodi Fang
- , Thomas D. Manes
- & Dan Jane-wit
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Article
| Open AccessVps11 and Vps18 of Vps-C membrane traffic complexes are E3 ubiquitin ligases and fine-tune signalling
Endosomal fusion depends on the HOPS and CORVET complexes but whether and how their subunits modulate signal transduction is not fully understood. Here, the authors show that the HOPS/CORVET subunits Vps11 and Vps18 are E3 ubiquitin ligases that are involved in the regulation of ERα signalling.
- Gregory Segala
- , Marcela A. Bennesch
- & Didier Picard
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Article
| Open AccessSNAREs define targeting specificity of trafficking vesicles by combinatorial interaction with tethering factors
Intracellular vesicle targeting is mediated by Rab GTPases that cooperate with phosphatidylinositides and SNARE proteins, which then facilitate membrane fusion. Here, the authors microinject artificial vesicles into HeLa cells and find that SNAREs play a more prominent role in targeting specificity of trafficking vesicles than previously known.
- Seiichi Koike
- & Reinhard Jahn
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Article
| Open AccessClassification of the human phox homology (PX) domains based on their phosphoinositide binding specificities
Phox homology (PX) domains are membrane interacting domains that bind to various lipids. Here authors screen all human PX domains systematically for their phospholipid preferences and define four classes and provide the basis for defining and predicting functional PX-membrane interactions.
- Mintu Chandra
- , Yanni K.-Y. Chin
- & Brett M. Collins
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Article
| Open AccessSecreted metalloproteases ADAMTS9 and ADAMTS20 have a non-canonical role in ciliary vesicle growth during ciliogenesis
Ciliogenesis is a complex process requiring hundreds of molecules, although few secreted proteins have been implicated. Here, the authors show that the secreted metalloproteases ADAMTS9 and ADAMTS20 intracellularly regulate ciliogenesis from unique periciliary vesicles with proteolytic activity.
- Sumeda Nandadasa
- , Caroline M. Kraft
- & Suneel S. Apte
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Article
| Open AccessTGNap1 is required for microtubule-dependent homeostasis of a subpopulation of the plant trans-Golgi network
The plant trans-Golgi network comprises functionally distinct subcompartments. Here Renna et al. show that the TGNap1 protein acts in microtubule-dependent biogenesis, tracking and function of a TGN subset, highlighting diversification within the plant TGN.
- Luciana Renna
- , Giovanni Stefano
- & Federica Brandizzi
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Article
| Open AccessAmino acids stimulate the endosome-to-Golgi trafficking through Ragulator and small GTPase Arl5
Amino acid levels are known to regulate anabolic and catabolic pathways. Here, the authors report that amino acids also affect membrane trafficking by stimulating endosome-to-Golgi retrograde trafficking and regulating cell surface localization of certain Golgi proteins through Ragulator and Arl5.
- Meng Shi
- , Bing Chen
- & Lei Lu
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Article
| Open AccessA mobile endocytic network connects clathrin-independent receptor endocytosis to recycling and promotes T cell activation
Endocytosis of T cell receptors (TCR) and their polarized recycling back to the plasma membrane is crucial for T cell activation; however, the underlying mechanisms remain unclear. Here the authors follow TCR and show that a mobile endocytic network connects clathrin-independent receptor endocytosis to recycling which is required for T cell activation.
- Ewoud B. Compeer
- , Felix Kraus
- & Jérémie Rossy
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Article
| Open AccessPhosphorylation of conserved phosphoinositide binding pocket regulates sorting nexin membrane targeting
Sorting nexin 3 (SNX3) is a phosphatidylinositol 3-phosphate binding protein that localizes to early endosomes. Here the authors use NMR to resolve SNX3′s membrane interactions, revealing that membrane binding is regulated through phosphorylation of a conserved serine by its lipid recognition site.
- Marc Lenoir
- , Cansel Ustunel
- & Michael Overduin
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Article
| Open AccessVps3 and Vps8 control integrin trafficking from early to recycling endosomes and regulate integrin-dependent functions
The CORVET complex is a multi-subunit complex that regulates fusion between early endosomes. Here the authors show that the CORVET subunits Vps3 and Vps8 also regulate vesicular transport from early to recycling endosomes and are required for recycling integrins to the plasma membrane.
- Caspar T. H. Jonker
- , Romain Galmes
- & Judith Klumperman
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Article
| Open AccessEndosomal phosphatidylserine is critical for the YAP signalling pathway in proliferating cells
Yes-associated protein (YAP) is a growth-promoting transcription co-activator that regulates the malignancy of various cancers, however its regulation is not fully understood. Here the authors show that phosphatdylserine at recycling endosomes regulates YAP signalling pathway.
- Tatsuyuki Matsudaira
- , Kojiro Mukai
- & Tomohiko Taguchi
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Article
| Open AccessAssay to visualize specific protein oxidation reveals spatio-temporal regulation of SHP2
Protein-tyrosine phosphatases (PTPs) are thought to be major targets of receptor-activated reactive oxygen species (ROS). Here the authors describe a method that allows the localized visualization of oxidized intermediates of PTPs inside cells during signaling, and provide support for the “redoxosome” model.
- Ryouhei Tsutsumi
- , Jana Harizanova
- & Benjamin G. Neel
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Article
| Open AccessSara phosphorylation state controls the dispatch of endosomes from the central spindle during asymmetric division
Asymmetric segregation of cell fate determinants during cell division governs daughter cell fate. Here the authors show that Sara endosomes, known to regulate Notch signalling, are targeted to the mitotic spindle and once phosphorylated are asymmetrically dispatched into a daughter cell to determine cell fate.
- Sylvain Loubéry
- , Alicia Daeden
- & Marcos Gonzalez-Gaitan
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Article
| Open AccessA Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance
Damaged mitochondria are normally cleared through canonical and alternative autophagy pathways. Here, the authors report that mitochondria can be cleared through an autophagy-independent endosomal-lysosomal pathway that depends on Parkin-dependent sequestration of mitochondria in Rab5-positive early endosomes.
- Babette C. Hammerling
- , Rita H. Najor
- & Åsa B. Gustafsson
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Article
| Open AccessArchitecture and mechanism of the late endosomal Rab7-like Ypt7 guanine nucleotide exchange factor complex Mon1–Ccz1
The Mon1-Ccz1 (MC1) complex is a Rab guanine nucleotide exchange factor (RabGEF) for Ypt7/Rab7 important for endosomal maturation. Here the authors present the biochemical and structural characterization of MC1, elucidating its catalytic mechanism and showing that MC1 represents novel class of RabGEFs.
- Stephan Kiontke
- , Lars Langemeyer
- & Daniel Kümmel
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Article
| Open AccessHS1BP3 negatively regulates autophagy by modulation of phosphatidic acid levels
Autophagy must be tightly controlled at each step of the process. Here the authors show that HS1BP3 binds phosphatidic acid (PA) at autophagosome precursors and negatively regulates autophagosome formation by modulating the activity and localization of the PA-producing enzyme phospholipase D1.
- Petter Holland
- , Helene Knævelsrud
- & Anne Simonsen