Subunit Organization and Rab Interactions of Vps-C Protein Complexes That Control Endolysosomal Membrane Traffic
Total Page:16
File Type:pdf, Size:1020Kb

Load more
Recommended publications
-
Vps8 Overexpression Inhibits HOPS- Dependent Trafficking Routes By
RESEARCH ADVANCE Vps8 overexpression inhibits HOPS- dependent trafficking routes by outcompeting Vps41/Lt Pe´ ter Lo˝ rincz1,2*, Lili Anna Kene´ z1, Sarolta To´ th1, Vikto´ ria Kiss3,A´ gnes Varga1, Tama´ s Csizmadia1, Zso´ fia Simon-Vecsei1, Ga´ bor Juha´ sz1,3* 1Department of Anatomy, Cell and Developmental Biology, Eo¨ tvo¨ s Lora´nd University, Budapest, Hungary; 2Premium Postdoctoral Research Program, Hungarian Academy of Sciences, Budapest, Hungary; 3Institute of Genetics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary Abstract Two related multisubunit tethering complexes promote endolysosomal trafficking in all eukaryotes: Rab5-binding CORVET that was suggested to transform into Rab7-binding HOPS. We have previously identified miniCORVET, containing Drosophila Vps8 and three shared core proteins, which are required for endosome maturation upstream of HOPS in highly endocytic cells (Lo˝rincz et al., 2016a). Here, we show that Vps8 overexpression inhibits HOPS-dependent trafficking routes including late endosome maturation, autophagosome-lysosome fusion, crinophagy and lysosome-related organelle formation. Mechanistically, Vps8 overexpression abolishes the late endosomal localization of HOPS-specific Vps41/Lt and prevents HOPS assembly. Proper ratio of Vps8 to Vps41 is thus critical because Vps8 negatively regulates HOPS by outcompeting Vps41. Endosomal recruitment of miniCORVET- or HOPS-specific subunits requires proper complex assembly, and Vps8/miniCORVET is dispensable for autophagy, crinophagy and lysosomal biogenesis. These data together indicate the recruitment of these complexes to target membranes independent of each other in Drosophila, rather than their transformation during *For correspondence: vesicle maturation. [email protected] (PL); DOI: https://doi.org/10.7554/eLife.45631.001 [email protected] (GJ) Competing interests: The authors declare that no competing interests exist. -
New Approaches to Functional Process Discovery in HPV 16-Associated Cervical Cancer Cells by Gene Ontology
Cancer Research and Treatment 2003;35(4):304-313 New Approaches to Functional Process Discovery in HPV 16-Associated Cervical Cancer Cells by Gene Ontology Yong-Wan Kim, Ph.D.1, Min-Je Suh, M.S.1, Jin-Sik Bae, M.S.1, Su Mi Bae, M.S.1, Joo Hee Yoon, M.D.2, Soo Young Hur, M.D.2, Jae Hoon Kim, M.D.2, Duck Young Ro, M.D.2, Joon Mo Lee, M.D.2, Sung Eun Namkoong, M.D.2, Chong Kook Kim, Ph.D.3 and Woong Shick Ahn, M.D.2 1Catholic Research Institutes of Medical Science, 2Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul; 3College of Pharmacy, Seoul National University, Seoul, Korea Purpose: This study utilized both mRNA differential significant genes of unknown function affected by the display and the Gene Ontology (GO) analysis to char- HPV-16-derived pathway. The GO analysis suggested that acterize the multiple interactions of a number of genes the cervical cancer cells underwent repression of the with gene expression profiles involved in the HPV-16- cancer-specific cell adhesive properties. Also, genes induced cervical carcinogenesis. belonging to DNA metabolism, such as DNA repair and Materials and Methods: mRNA differential displays, replication, were strongly down-regulated, whereas sig- with HPV-16 positive cervical cancer cell line (SiHa), and nificant increases were shown in the protein degradation normal human keratinocyte cell line (HaCaT) as a con- and synthesis. trol, were used. Each human gene has several biological Conclusion: The GO analysis can overcome the com- functions in the Gene Ontology; therefore, several func- plexity of the gene expression profile of the HPV-16- tions of each gene were chosen to establish a powerful associated pathway, identify several cancer-specific cel- cervical carcinogenesis pathway. -
Diversification of CORVET Tethers Facilitates Transport Complexity in Tetrahymena Thermophila Daniela Sparvoli1,*, Martin Zoltner2,3, Chao-Yin Cheng1, Mark C
© 2020. Published by The Company of Biologists Ltd | Journal of Cell Science (2020) 133, jcs238659. doi:10.1242/jcs.238659 RESEARCH ARTICLE Diversification of CORVET tethers facilitates transport complexity in Tetrahymena thermophila Daniela Sparvoli1,*, Martin Zoltner2,3, Chao-Yin Cheng1, Mark C. Field2 and Aaron P. Turkewitz1,‡ ABSTRACT Key determinants for ensuring productive membrane interactions In endolysosomal networks, two hetero-hexameric tethers called are SNARE proteins, with distinct paralogs present at each HOPS and CORVET are found widely throughout eukaryotes. The compartment (Gerst, 1999). SNARE complex assembly drives unicellular ciliate Tetrahymena thermophila possesses elaborate formation of a fusion pore, together with complexes called tethers endolysosomal structures, but curiously both it and related protozoa that act upstream of SNAREs (Baker and Hughson, 2016). The lack the HOPS tether and several other trafficking proteins, while homotypic-fusion-and-protein-sorting (HOPS) and class-C-core- retaining the related CORVET complex. Here, we show that vacuole/endosome-tethering (CORVET) complexes are cytoplasmic Tetrahymena encodes multiple paralogs of most CORVET hetero-hexamers that bridge compartments by binding Rab GTPases at subunits, which assemble into six distinct complexes. Each two membranes, and subsequently chaperoning SNARE assembly complex has a unique subunit composition and, significantly, shows (Baker and Hughson, 2016; Horazdovsky et al., 1996; Nickerson unique localization, indicating participation -
Variation in Protein Coding Genes Identifies Information
bioRxiv preprint doi: https://doi.org/10.1101/679456; this version posted June 21, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Animal complexity and information flow 1 1 2 3 4 5 Variation in protein coding genes identifies information flow as a contributor to 6 animal complexity 7 8 Jack Dean, Daniela Lopes Cardoso and Colin Sharpe* 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Institute of Biological and Biomedical Sciences 25 School of Biological Science 26 University of Portsmouth, 27 Portsmouth, UK 28 PO16 7YH 29 30 * Author for correspondence 31 [email protected] 32 33 Orcid numbers: 34 DLC: 0000-0003-2683-1745 35 CS: 0000-0002-5022-0840 36 37 38 39 40 41 42 43 44 45 46 47 48 49 Abstract bioRxiv preprint doi: https://doi.org/10.1101/679456; this version posted June 21, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Animal complexity and information flow 2 1 Across the metazoans there is a trend towards greater organismal complexity. How 2 complexity is generated, however, is uncertain. Since C.elegans and humans have 3 approximately the same number of genes, the explanation will depend on how genes are 4 used, rather than their absolute number. -
CORVET, CHEVI and HOPS – Multisubunit Tethers of the Endo
© 2019. Published by The Company of Biologists Ltd | Journal of Cell Science (2019) 132, jcs189134. doi:10.1242/jcs.189134 REVIEW SUBJECT COLLECTION: CELL BIOLOGY AND DISEASE CORVET, CHEVI and HOPS – multisubunit tethers of the endo-lysosomal system in health and disease Jan van der Beek‡, Caspar Jonker*,‡, Reini van der Welle, Nalan Liv and Judith Klumperman§ ABSTRACT contact between two opposing membranes and pull them close Multisubunit tethering complexes (MTCs) are multitasking hubs that together to allow interactions between SNARE proteins (Murray form a link between membrane fusion, organelle motility and signaling. et al., 2016). SNARE assembly then provides additional fusion CORVET, CHEVI and HOPS are MTCs of the endo-lysosomal system. specificity and drives the actual fusion process (Ohya et al., 2009; They regulate the major membrane flows required for endocytosis, Stroupe et al., 2009). In this Review, we focus on the role of tethering lysosome biogenesis, autophagy and phagocytosis. In addition, proteins in endo-lysosomal fusion events. individual subunits control complex-independent transport of specific Tethering proteins can be divided into two main groups: long cargoes and exert functions beyond tethering, such as attachment to coiled-coil proteins (Gillingham and Munro, 2003) and microtubules and SNARE activation. Mutations in CHEVI subunits multisubunit tethering complexes (MTCs). MTCs form a lead to arthrogryposis, renal dysfunction and cholestasis (ARC) heterogenic group of protein complexes that consist of up to ten ∼ syndrome, while defects in CORVET and, particularly, HOPS are subunits resulting in a general length of 50 nm (Brocker et al., associated with neurodegeneration, pigmentation disorders, liver 2012; Chou et al., 2016; Hsu et al., 1998; Lürick et al., 2018; Ren malfunction and various forms of cancer. -
S41467-019-09800-Y.Pdf
ARTICLE https://doi.org/10.1038/s41467-019-09800-y OPEN Vps11 and Vps18 of Vps-C membrane traffic complexes are E3 ubiquitin ligases and fine-tune signalling Gregory Segala 1, Marcela A. Bennesch1, Nastaran Mohammadi Ghahhari1, Deo Prakash Pandey1,3, Pablo C. Echeverria 1, François Karch 2, Robert K. Maeda2 & Didier Picard 1 1234567890():,; In response to extracellular signals, many signalling proteins associated with the plasma membrane are sorted into endosomes. This involves endosomal fusion, which depends on the complexes HOPS and CORVET. Whether and how their subunits themselves modulate signal transduction is unknown. We show that Vps11 and Vps18 (Vps11/18), two common subunits of the HOPS/CORVET complexes, are E3 ubiquitin ligases. Upon overexpression of Vps11/ Vps18, we find perturbations of ubiquitination in signal transduction pathways. We specifi- cally demonstrate that Vps11/18 regulate several signalling factors and pathways, including Wnt, estrogen receptor α (ERα), and NFκB. For ERα, we demonstrate that the Vps11/18- mediated ubiquitination of the scaffold protein PELP1 impairs the activation of ERα by c-Src. Thus, proteins involved in membrane traffic, in addition to performing their well-described role in endosomal fusion, fine-tune signalling in several different ways, including through ubiquitination. 1 Département de Biologie Cellulaire, Université de Genève, Sciences III, 30 quai Ernest-Ansermet, 1211 Genève, Switzerland. 2 Département de Génétique et Évolution, Université de Genève, Sciences III, 30 quai Ernest-Ansermet, -
Subunit Organisation of in Vitro Reconstituted HOPS and CORVET Multisubunit Membrane Tethering Complexes
Subunit Organisation of In Vitro Reconstituted HOPS and CORVET Multisubunit Membrane Tethering Complexes Zhong Guo1, Wayne Johnston1, Oleksiy Kovtun1, Sergey Mureev1, Cornelia Bröcker2, Christian Ungermann2, Kirill Alexandrov1* 1 Department of Cell and Molecular Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia, 2 Department of Biology/Chemisty, University of Osnabrück, Osnabrück, Germany Abstract Biochemical and structural analysis of macromolecular protein assemblies remains challenging due to technical difficulties in recombinant expression, engineering and reconstitution of multisubunit complexes. Here we use a recently developed cell-free protein expression system based on the protozoan Leishmania tarentolae to produce in vitro all six subunits of the 600 kDa HOPS and CORVET membrane tethering complexes. We demonstrate that both subcomplexes and the entire HOPS complex can be reconstituted in vitro resulting in a comprehensive subunit interaction map. To our knowledge this is the largest eukaryotic protein complex in vitro reconstituted to date. Using the truncation and interaction analysis, we demonstrate that the complex is assembled through short hydrophobic sequences located in the C-terminus of the individual Vps subunits. Based on this data we propose a model of the HOPS and CORVET complex assembly that reconciles the available biochemical and structural data. Citation: Guo Z, Johnston W, Kovtun O, Mureev S, Bröcker C, et al. (2013) Subunit Organisation of In Vitro Reconstituted HOPS and CORVET Multisubunit Membrane Tethering Complexes. PLoS ONE 8(12): e81534. doi:10.1371/journal.pone.0081534 Editor: Vladimir N. Uversky, University of South Florida College of Medicine, United States of America Received July 11, 2013; Accepted October 14, 2013; Published December 2, 2013 Copyright: © 2013 Guo et al. -
Gene Is Associated with Neuroaxonal Dystrophy in Rottweiler Dogs
UC Davis UC Davis Previously Published Works Title A Missense Mutation in the Vacuolar Protein Sorting 11 (VPS11) Gene Is Associated with Neuroaxonal Dystrophy in Rottweiler Dogs. Permalink https://escholarship.org/uc/item/15j103gh Journal G3 (Bethesda, Md.), 8(8) ISSN 2160-1836 Authors Lucot, Katherine L Dickinson, Peter J Finno, Carrie J et al. Publication Date 2018-07-31 DOI 10.1534/g3.118.200376 Peer reviewed eScholarship.org Powered by the California Digital Library University of California INVESTIGATION A Missense Mutation in the Vacuolar Protein Sorting 11 (VPS11) Gene Is Associated with Neuroaxonal Dystrophy in Rottweiler Dogs Katherine L. Lucot,* Peter J. Dickinson,† Carrie J. Finno,* Tamer A. Mansour,* Anna Letko,‡ Katherine M. Minor,§ James R. Mickelson,§ Cord Drögemüller,‡ C. Titus Brown,* and Danika L. Bannasch*,1 *Departments of Population Health and Reproduction, and †Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, ‡Department of Clinical Research and Veterinary Public Health, § University of Bern, 3001 Bern, Switzerland, and Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Minneapolis, MN 55455 ORCID ID: 0000-0001-9773-522X (C.D.) ABSTRACT Canine neuroaxonal dystrophy (NAD) is a recessive, degenerative neurological disease of KEYWORDS young adult Rottweiler dogs (Canis lupus familiaris) characterized pathologically by axonal spheroids pri- autophagy marily targeting sensory axon terminals. A genome-wide association study of seven Rottweilers affected canine with NAD and 42 controls revealed a significantly associated region on canine chromosome 5 (CFA 5). lysosome Homozygosity within the associated region narrowed the critical interval to a 4.46 Mb haplotype neurodegenerative (CFA5:11.28 Mb – 15.75 Mb; CanFam3.1) that associated with the phenotype. -
HOPS-Dependent Endosomal Fusion Required for Efficient Cytosolic Delivery of Therapeutic Peptides and Small Proteins
HOPS-dependent endosomal fusion required for efficient cytosolic delivery of therapeutic peptides and small proteins Angela Steinauera, Jonathan R. LaRochelleb, Susan L. Knoxa, Rebecca F. Wissnera, Samuel Berryc, and Alanna Schepartza,b,1 aDepartment of Chemistry, Yale University, New Haven, CT 06520-8107; bDepartment of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520-8103; and cDepartment of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8114 Edited by James A. Wells, University of California, San Francisco, CA, and approved November 26, 2018 (received for review July 17, 2018) Protein therapeutics represent a significant and growing compo- Recently, we discovered that, when added to cells, certain small, nent of the modern pharmacopeia, but their potential to treat folded miniature proteins (9, 10) derived from avian pancreatic human disease is limited because most proteins fail to traffic polypeptide (aPP) or an isolated zinc-finger (ZF) domain, are across biological membranes. Recently, we discovered a class of taken up into the endocytic pathway and subsequently released cell-permeant miniature proteins (CPMPs) containing a precisely into the cytosol with unprecedented efficiencies (11, 12). The most defined, penta-arginine (penta-Arg) motif that traffics readily to effective molecules are defined by a discrete array of five arginine the cytosol and nucleus of mammalian cells with efficiencies that residues on a folded α-helix (13); we refer to these molecules as rival those of hydrocarbon-stapled peptides active in animals and cell-permeant miniature proteins (CPMPs). Treatment of HeLa man. Like many cell-penetrating peptides (CPPs), CPMPs enter the cells in culture with the CPMP ZF5.3 leads to a ZF5.3 concen- endocytic pathway; the difference is that CPMPs containing a penta- tration in the cytosol that is roughly 67% of the extracellular in- Arg motif are released efficiently from endosomes, while other CPPs cubation concentration; this value is at least 10-fold higher than are not. -
Agricultural University of Athens
ΓΕΩΠΟΝΙΚΟ ΠΑΝΕΠΙΣΤΗΜΙΟ ΑΘΗΝΩΝ ΣΧΟΛΗ ΕΠΙΣΤΗΜΩΝ ΤΩΝ ΖΩΩΝ ΤΜΗΜΑ ΕΠΙΣΤΗΜΗΣ ΖΩΙΚΗΣ ΠΑΡΑΓΩΓΗΣ ΕΡΓΑΣΤΗΡΙΟ ΓΕΝΙΚΗΣ ΚΑΙ ΕΙΔΙΚΗΣ ΖΩΟΤΕΧΝΙΑΣ ΔΙΔΑΚΤΟΡΙΚΗ ΔΙΑΤΡΙΒΗ Εντοπισμός γονιδιωματικών περιοχών και δικτύων γονιδίων που επηρεάζουν παραγωγικές και αναπαραγωγικές ιδιότητες σε πληθυσμούς κρεοπαραγωγικών ορνιθίων ΕΙΡΗΝΗ Κ. ΤΑΡΣΑΝΗ ΕΠΙΒΛΕΠΩΝ ΚΑΘΗΓΗΤΗΣ: ΑΝΤΩΝΙΟΣ ΚΟΜΙΝΑΚΗΣ ΑΘΗΝΑ 2020 ΔΙΔΑΚΤΟΡΙΚΗ ΔΙΑΤΡΙΒΗ Εντοπισμός γονιδιωματικών περιοχών και δικτύων γονιδίων που επηρεάζουν παραγωγικές και αναπαραγωγικές ιδιότητες σε πληθυσμούς κρεοπαραγωγικών ορνιθίων Genome-wide association analysis and gene network analysis for (re)production traits in commercial broilers ΕΙΡΗΝΗ Κ. ΤΑΡΣΑΝΗ ΕΠΙΒΛΕΠΩΝ ΚΑΘΗΓΗΤΗΣ: ΑΝΤΩΝΙΟΣ ΚΟΜΙΝΑΚΗΣ Τριμελής Επιτροπή: Aντώνιος Κομινάκης (Αν. Καθ. ΓΠΑ) Ανδρέας Κράνης (Eρευν. B, Παν. Εδιμβούργου) Αριάδνη Χάγερ (Επ. Καθ. ΓΠΑ) Επταμελής εξεταστική επιτροπή: Aντώνιος Κομινάκης (Αν. Καθ. ΓΠΑ) Ανδρέας Κράνης (Eρευν. B, Παν. Εδιμβούργου) Αριάδνη Χάγερ (Επ. Καθ. ΓΠΑ) Πηνελόπη Μπεμπέλη (Καθ. ΓΠΑ) Δημήτριος Βλαχάκης (Επ. Καθ. ΓΠΑ) Ευάγγελος Ζωίδης (Επ.Καθ. ΓΠΑ) Γεώργιος Θεοδώρου (Επ.Καθ. ΓΠΑ) 2 Εντοπισμός γονιδιωματικών περιοχών και δικτύων γονιδίων που επηρεάζουν παραγωγικές και αναπαραγωγικές ιδιότητες σε πληθυσμούς κρεοπαραγωγικών ορνιθίων Περίληψη Σκοπός της παρούσας διδακτορικής διατριβής ήταν ο εντοπισμός γενετικών δεικτών και υποψηφίων γονιδίων που εμπλέκονται στο γενετικό έλεγχο δύο τυπικών πολυγονιδιακών ιδιοτήτων σε κρεοπαραγωγικά ορνίθια. Μία ιδιότητα σχετίζεται με την ανάπτυξη (σωματικό βάρος στις 35 ημέρες, ΣΒ) και η άλλη με την αναπαραγωγική -
Coexpression Networks Based on Natural Variation in Human Gene Expression at Baseline and Under Stress
University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations Fall 2010 Coexpression Networks Based on Natural Variation in Human Gene Expression at Baseline and Under Stress Renuka Nayak University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Computational Biology Commons, and the Genomics Commons Recommended Citation Nayak, Renuka, "Coexpression Networks Based on Natural Variation in Human Gene Expression at Baseline and Under Stress" (2010). Publicly Accessible Penn Dissertations. 1559. https://repository.upenn.edu/edissertations/1559 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/1559 For more information, please contact [email protected]. Coexpression Networks Based on Natural Variation in Human Gene Expression at Baseline and Under Stress Abstract Genes interact in networks to orchestrate cellular processes. Here, we used coexpression networks based on natural variation in gene expression to study the functions and interactions of human genes. We asked how these networks change in response to stress. First, we studied human coexpression networks at baseline. We constructed networks by identifying correlations in expression levels of 8.9 million gene pairs in immortalized B cells from 295 individuals comprising three independent samples. The resulting networks allowed us to infer interactions between biological processes. We used the network to predict the functions of poorly-characterized human genes, and provided some experimental support. Examining genes implicated in disease, we found that IFIH1, a diabetes susceptibility gene, interacts with YES1, which affects glucose transport. Genes predisposing to the same diseases are clustered non-randomly in the network, suggesting that the network may be used to identify candidate genes that influence disease susceptibility. -
Integrative Functional Analyses of the Neurodegenerative Disease-Associated TECPR2 Gene Reveal Its Diverse Roles
Integrative functional analyses of the neurodegenerative disease-associated TECPR2 gene reveal its diverse roles Ido Shalev Ben-Gurion University of the Negev Judith Somekh University of Haifa Alal Eran ( [email protected] ) Ben-Gurion University of the Negev https://orcid.org/0000-0001-6784-7597 Research article Keywords: Integrative functional analysis, neurodegenerative disorders, autophagy, ribosome, TECPR2 Posted Date: January 30th, 2020 DOI: https://doi.org/10.21203/rs.2.22274/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/23 Abstract Background Loss of tectonin β-propeller repeat-containing 2 (TECPR2) function has been implicated in an array of neurodegenerative disorders, yet its physiological function remains largely unknown. Understanding TECPR2 function is essential for developing much needed precision therapeutics for TECPR2-related diseases. Methods We leveraged the considerable amounts of functional data to obtain a comprehensive perspective of the role of TECPR2 in health and disease. We integrated expression patterns, population variation, phylogenetic proling, protein-protein interactions, and regulatory network data for a minimally biased multimodal functional analysis. Genes and proteins linked to TECPR2 via multiple lines of evidence were subject to functional enrichment analyses to identify molecular mechanisms involving TECPR2. Results TECPR2 was found to be part of a tight neurodevelopmental gene expression program that includes KIF1A, ATXN1, TOM1L2, and FA2H, all implicated in neurological diseases. Functional enrichment analyses of TECPR2-related genes converged on a role in late autophagy and ribosomal processes. Large-scale population variation data demonstrated that this role is nonredundant. Conclusions TECPR2 might serve as an indicator for the energy balance between protein synthesis and autophagy, and a marker for diseases associated with their imbalance, such as Alzheimer’s disease, Huntington’s disease, and various cancers.