DOCSLIB.ORG

Ubiquitin-Dependent Sorting in Endocytosis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Ubiquitin-Dependent Sorting in Endocytosis Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Ubiquitin-Dependent Sorting in Endocytosis Robert C. Piper1, Ivan Dikic2, and Gergely L. Lukacs3 1Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242 2Buchmann Institute for Molecular Life Sciences and Institute of Biochemistry II, Goethe University School of Medicine, D-60590 Frankfurt, Germany 3Department of Physiology, McGill University, Montre´al, Que´bec H3G 1Y6, Canada Correspondence: [email protected] When ubiquitin (Ub) is attached to membrane proteins on the plasma membrane, it directs them through a series of sorting steps that culminate in their delivery to the lumen of the lysosome where they undergo complete proteolysis. Ubiquitin is recognized by a series of complexes that operate at a number of vesicle transport steps. Ubiquitin serves as a sorting signal for internalization at the plasma membrane and is the major signal for incorporation into intraluminal vesicles of multivesicular late endosomes. The sorting machineries that catalyze these steps can bind Ub via a variety of Ub-binding domains. At the same time, many of these complexes are themselves ubiquitinated, thus providing a plethora of potential mechanisms to regulate their activity. Here we provide an overview of how membrane proteins are selected for ubiquitination and deubiquitination within the endocytic pathway and how that ubiquitin signal is interpreted by endocytic sorting machineries. HOW PROTEINS ARE SELECTED FOR distinctions concerning different types of ligas- UBIQUITINATION es, their specificity for forming particular poly- Ub chains, and even the kinds of residues in biquitin (Ub) is covalently attached to sub- substrate proteins that can be ubiquitin modi- Ustrate proteins by the concerted action of fied, have been blurred with the discovery of E2-conjugating enzymes and E3 ligases (Var- mixed poly-Ub chains, new enzymatic mecha- shavsky 2012). Most of the specificity and reg- nisms for Ub transfer, and ubiquitination of ulation of ubiquitination is at the level of the E3 nonlysine residues (Kulathu and Komander ligases, which vastly outnumber the E2-conju- 2012; Wenzel and Klevit 2012; McDowell and gating enzymes. Ubiquitination results from the Philpott 2013). Nonetheless, in basic terms, Ub transfer of Ub, held either by the E2 or in some ligases function as platforms that coordinate cases by the E3 as a high-energy thioester bond, substrate recognition with Ub transfer as well onto a substrate protein, typically on the termi- as configuring poly-Ub chain topology by the nal amide of a substrate acceptor lysine side E2-conjugating enzyme. Substrates can be chain. Owing to the intense interest in the ubiq- bound directly by the E3 ligase or by adaptor uitination system, many of the simple rules and proteins that in turn bind to ligases, and selec- Editors: Sandra L. Schmid, Alexander Sorkin, and Marino Zerial Additional Perspectives on Endocytosis available at www.cshperspectives.org Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a016808 Cite this article as Cold Spring Harb Perspect Biol 2014;6:a016808 1 Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press R.C. Piper et al. tion of substrate residues that undergo ubiqui- and Ubc5-conjugating enzymes (Haglund et al. tination is accomplished by the particular archi- 2003; Huang et al. 2006, 2007). Other RTKs, tecture of the substrate/ligase complex that de- such as those for hepatocyte growth factor termines the orientation to the thioester-linked (HGF), vascular endothelial growth factor re- Ub. The ubiquitin-peptidases (deubiquitinat- ceptor (VEGFR-1), and platelet-derived growth ing enzymes [DUbs]) that remove Ub from sub- factor (PDGF) receptors, also rapidly undergo strates also play critical roles in controlling the ligand-stimulated ubiquitination by Cbl (Hag- level of substrate protein ubiquitination. Of the lund and Dikic 2012). Cbl has other targets as roughly 90 DUbs in humans and 20 DUbs in well, such as integrins, which connect cellsto the yeast, many are found associated with Ub ligases extracellular matrix to control cell adhesion, mi- or with the endocytic machinery that recognizes gration, and proliferation. Ubiquitination of in- ubiquitinated proteins, thus positioning DUbs tegrins promotes their lysosomal degradation, to regulate the ubiquitination process at a vari- which in turn prevents the accumulation of li- ety of junctures (Table 1) (Clague et al. 2012). gand-bound integrins within endosomes that Ubiquitination of cell-surface membrane might go on to form nonproductive adhesion proteins initiates their journey to lysosomes sites upon exocytosis (Lobert et al. 2010). Ubiq- for degradation (Fig. 1). Ub does this in part by uitination of the a5 subunit of the a5b1 fibro- serving as a signal for internalization and sub- nectin integrin receptor is triggered by the acti- sequent sorting into the interior of lysosomes. vation of the FGFR2 (fibroblast growth factor In general, the selection of membrane proteins receptor 2) that induces the recruitment of c- for ubiquitination can either be due to a pro- Cbl in osteoblasts (Kaabeche et al. 2005). grammed biological response (such as ligand- A group of Ub ligases with emerging impor- mediated receptor down-regulation) or as a way tance are the membrane-associated RING-CH to remove aberrantly folded or damaged pro- (MARCH) ligases, encompassing a family of teins from the cell surface as a quality-control 11 RING-CH E3 Ub ligases (Nathan and Lehner mechanism. 2009). MARCH ligases are orthologs of the Ka- Ubiquitination of receptor tyrosine kinases posi sarcoma-associated herpesvirus (KSVH) (RTKs) is one of the most studied examples for immunoevasion ligases K3 and K5 and con- how Ub traffics proteins through the endocytic tain two transmembrane segments and a cyto- system. RTKs consist of .50 members in hu- solic RING-CH domain (Boname and Lehner mans and have an essential role in controlling 2011). Endogenous or overexpressed MARCH cell proliferation and migration (Lemmon and ligases play a key role in the ubiquitination-de- Schlessinger 2010). Ligand-induced activation pendent down-regulation and lysosomal degra- of RTKs leads to rapid ubiquitination of several dation of a variety of cell-surface receptors (e.g., RTKs at the PM by one of the Cbl (for Cas-Br-M MHC-I; K3, K5, MARCH-9 and -4, MHC-II; ectopic retroviral transforming sequence) RING MARCH-2 and -8, CD4, CD44, and CD98; (really interesting new gene)-type E3 ubiquitin MARCH-4 and -8) (Nathan and Lehner 2009). ligase family members (Levkowitz et al. 1999). The mechanism used by these integral mem- A canonical example is the epidermal growth brane ligases to recognize other membrane factor receptor (EGFR), which upon activa- protein substrates is intriguing and appears to tion and autophosphorylation of pY1045, can involve recognition of hydrophobic transmem- now bind the amino-terminal pY-binding do- brane as well as the proximal regions juxtaposed main (PTB) of Cbl. In addition, receptor ubiq- to these transmembrane-spanning segments. uitination is augmented by the adaptor pro- A transmembrane hydrophobic patch in concert tein, growth factor receptor-bound protein 2 with a membrane proximal Lys residue at (GRB2), a constitutive partner of Cbl that binds the exofacial interface of HLA-DR constitutes to other pY residues of the EGFR. This facilitates key elements of the recognition surface for multiple-mono- and Lys63-linked polyubiqui- MARCH-8, whereas the Ub-acceptor Lys resi- tination in a manner dependent on the Ubc4- due has to be located at the proximity of the 2 Cite this article as Cold Spring Harb Perspect Biol 2014;6:a016808 Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Ubiquitin-Dependent Sorting in Endocytosis Table 1. Established and emerging proteins involved in ubiquitin-dependent control of the endocytic system Function and characteristics References Ub ligases Nedd4-2 Member of the larger family of HECT-type ligases that includes Fotia et al. 2004; Zhou NEDD4-1 (ITCH/AIP4), WWP1, WWP2, SMURF1, et al. 2007 SMURF2, NEDL1/HECW1, and NEDL2; ubiquitinates cargo such as ENaC and voltge-gated sodium channels. Itch Ubiquitinates CXCR-4 and ErbB-4; also ubiquitinates Angers et al. 2004; nonmembrane proteins such as endophillin and PI4-kinase Bhandari et al. 2007; type Iia that regulate endocytosis. Sundvall et al. 2008; Mossinger et al. 2012 Rsp5 The sole member of the Nedd4 family in yeast; responsible for Belgareh-Touze et al. ubiquitinating the vast majority of membrane proteins that 2008 are degraded within vacuole/lysosome. Cbl Major ligase that targets a broad range of receptor tyrosine Lipkowitz and Weissman kinases. 2011 SCF (b-TRCP) Ubiquitinates the growth hormone receptor, which has a motif van Kerkhof et al. 2011; that mimics the phosphorylated recognition motif that is da Silva Almeida et al. found within other SCF (b-TRCP) substrates. 2013 CHIP Modifies damaged conformationally defective proteins in the Apaja et al. 2010; plasma membrane to stimulate their lysosomal degradation Okiyoneda et al. 2010 and also misfolded proteins in the ER to stimulate their degradation in the proteasome. MARCH1 Member of the family of membrane-associated RING-CH Ishido et al. 2009 ligases; ubiquitinates MHC-II complex. MARCH2 Can target CFTR and b2-adrenergic receptors for lysosomal Han et al. 2012; Cheng degradation. and Guggino 2013 MARCH4 Targets MHC-I for degradation. Ishido et al. 2009 MARCH8 Targets TRAIL-R1, transferrin receptor, type I IL-1 receptor, Eyster et al. 2011; Fujita CD44, and CD96. et al. 2013; van de Kooij et al. 2013 IDOL Inducible degrader of the LDLR targets members of the LDL Zelcer et al. 2009 receptor family. MAGE-L2- Targets the Wiskott-Aldrich syndrome protein member WASH Hao et al. 2013 TRIM27 to regulate activity of retromer complex.
Load more

Recommended publications
  • Trafficking Routes to the Plant Vacuole: Connecting Alternative and Classical Pathways
    This is a repository copy of Trafficking routes to the plant vacuole: connecting alternative and classical pathways. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/124374/ Version: Accepted Version Article: Di Sansebastiano, GP, Barozzi, F, Piro, G et al. (2 more authors) (2018) Trafficking routes to the plant vacuole: connecting alternative and classical pathways. Journal of Experimental Botany, 69 (1). pp. 79-90. ISSN 0022-0957 https://doi.org/10.1093/jxb/erx376 © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology. This is an author produced version of a paper published in Journal of Experimental Botany. Uploaded in accordance with the publisher's self-archiving policy. Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item. Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ 1 Trafficking routes to the Plant Vacuole: 2 connecting alternative and classical pathways. 3 4 Gian Pietro Di Sansebastiano1*, Fabrizio Barozzi1, Gabriella Piro1, Jurgen Denecke2 and 5 Carine de Marcos Lousa2,3 * 6 1.! DiSTeBA (Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali), 7 University of Salento, Campus ECOTEKNE, 73100 Lecce, Italy; 8 [email protected] and [email protected].
    [Show full text]
  • Sorting Nexins in Protein Homeostasis Sara E. Hanley1,And Katrina F
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 6 November 2020 doi:10.20944/preprints202011.0241.v1 Sorting nexins in protein homeostasis Sara E. Hanley1,and Katrina F. Cooper2* 1Department of Molecular Biology, Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ, 08084, USA 1 [email protected] 2 [email protected] * [email protected] Tel: +1 (856)-566-2887 1Department of Molecular Biology, Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ, 08084, USA Abstract: Sorting nexins (SNXs) are a highly conserved membrane-associated protein family that plays a role in regulating protein homeostasis. This family of proteins is unified by their characteristic phox (PX) phosphoinositides binding domain. Along with binding to membranes, this family of SNXs also comprises a diverse array of protein-protein interaction motifs that are required for cellular sorting and protein trafficking. SNXs play a role in maintaining the integrity of the proteome which is essential for regulating multiple fundamental processes such as cell cycle progression, transcription, metabolism, and stress response. To tightly regulate these processes proteins must be expressed and degraded in the correct location and at the correct time. The cell employs several proteolysis mechanisms to ensure that proteins are selectively degraded at the appropriate spatiotemporal conditions. SNXs play a role in ubiquitin-mediated protein homeostasis at multiple levels including cargo localization, recycling, degradation, and function. In this review, we will discuss the role of SNXs in three different protein homeostasis systems: endocytosis lysosomal, the ubiquitin-proteasomal, and the autophagy-lysosomal system. The highly conserved nature of this protein family by beginning with the early research on SNXs and protein trafficking in yeast and lead into their important roles in mammalian systems.
    [Show full text]
  • Direct Lysosome-Based Autophagy of Lipid Droplets in Hepatocytes
    Direct lysosome-based autophagy of lipid droplets in hepatocytes Ryan J. Schulzea,b,1, Eugene W. Kruegera,b,1, Shaun G. Wellera,b, Katherine M. Johnsona,b, Carol A. Caseyc, Micah B. Schotta,b, and Mark A. McNivena,b,2 aDepartment of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905; bDivision of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905; and cDepartment of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198 Edited by Tobias C. Walther, Harvard School of Public Health, Boston, MA, and accepted by Editorial Board Member Joseph L. Goldstein October 13, 2020 (received for review June 4, 2020) Hepatocytes metabolize energy-rich cytoplasmic lipid droplets (LDs) process that appears to play an especially important role in the in the lysosome-directed process of autophagy. An organelle- degradation of hepatocellular LDs (15). A selective form of LD- selective form of this process (macrolipophagy) results in the engulf- centric autophagy known as lipophagy is thought to involve the ment of LDs within double-membrane delimited structures (auto- recognition of as-of-yet unidentified LD-specific receptors to phagosomes) before lysosomal fusion. Whether this is an promote the localized assembly and extension of a sequestering exclusive autophagic mechanism used by hepatocytes to catabolize phagophore around the perimeter of the LD (16, 17). How this LDs is unclear. It is also unknown whether lysosomes alone might be phagophore is targeted to (and extended around) the LD surface to sufficient to mediate LD turnover in the absence of an autophago- facilitate lipophagy remains unclear. Once fully enclosed, the somal intermediate.
    [Show full text]
  • ARCHAEAL EVOLUTION Evolutionary Insights from the Vikings
    RESEARCH HIGHLIGHTS Nature Reviews Microbiology | Published online 16 Jan 2017; doi:10.1038/nrmicro.2016.198 ARCHAEAL EVOLUTION Evolutionary insights from the Vikings The emergence of the eukaryotic cell ASGARD — after the invisible the closest known homologue of during evolution gave rise to all com- ‘Gods of Asgard’ in Norse mythology. eukaryotic epsilon DNA polymerases primordial plex life forms on Earth, including The superphylum consists of the identified thus far. eukaryotic multicellular organisms such as ani- previously identified Lokiarchaeota Members of the ASGARD super- mals, plants and fungi. However, the and Thorarchaeota phyla, and the phylum were particularly enriched vesicular and origin of eukaryotes and their char- newly identified Odinarchaeota and for eukaryotic signature proteins trafficking acteristic structural complexity has Heimdallarchaeota phyla. Using that are involved in intracellular components remained a mystery. The most recent phylogenomics, they discovered trafficking and secretion. Several are derived insights into eukaryogenesis support a strong phylogenetic association proteins contained domain signatures the endosymbiotic theory, which between ASGARD lineages and of eukaryotic transport protein from our proposes that the first eukaryotic eukaryotes that placed the eukaryote particle (TRAPP) complexes, which archaeal cell arose from archaea through the lineage in close proximity to the are involved in transport from the ancestor acquisition of an alphaproteobacterial ASGARD superphylum. endoplasmic
    [Show full text]
  • Retromer-Mediated Endosomal Protein Sorting: the Role of Unstructured Domains ⇑ Aamir S
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 589 (2015) 2620–2626 journal homepage: www.FEBSLetters.org Review Retromer-mediated endosomal protein sorting: The role of unstructured domains ⇑ Aamir S. Mukadam, Matthew N.J. Seaman Cambridge Institute for Medical Research, Dept. of Clinical Biochemistry, University of Cambridge, Wellcome Trust/MRC Building, Addenbrookes Hospital, Cambridge CB2 0XY, United Kingdom article info abstract Article history: The retromer complex is a key element of the endosomal protein sorting machinery that is con- Received 6 May 2015 served through evolution and has been shown to play a role in diseases such as Alzheimer’s disease Revised 21 May 2015 and Parkinson’s disease. Through sorting various membrane proteins (cargo), the function of retro- Accepted 26 May 2015 mer complex has been linked to physiological processes such as lysosome biogenesis, autophagy, Available online 10 June 2015 down regulation of signalling receptors and cell spreading. The cargo-selective trimer of retromer Edited by Wilhelm Just recognises membrane proteins and sorts them into two distinct pathways; endosome-to-Golgi retrieval and endosome-to-cell surface recycling and additionally the cargo-selective trimer func- tions as a hub to recruit accessory proteins to endosomes where they may regulate and/or facilitate Keywords: Retromer retromer-mediated endosomal proteins sorting. Unstructured domains present in cargo proteins or Endosome accessory factors play key roles in both these aspects of retromer function and will be discussed in Sorting this review. FAM21 Ó 2015 Federation of European Biochemical Societies.
    [Show full text]
  • Why Cells and Viruses Cannot Survive Without an ESCRT
    cells Review Why Cells and Viruses Cannot Survive without an ESCRT Arianna Calistri * , Alberto Reale, Giorgio Palù and Cristina Parolin Department of Molecular Medicine, University of Padua, 35121 Padua, Italy; [email protected] (A.R.); [email protected] (G.P.); [email protected] (C.P.) * Correspondence: [email protected] Abstract: Intracellular organelles enwrapped in membranes along with a complex network of vesicles trafficking in, out and inside the cellular environment are one of the main features of eukaryotic cells. Given their central role in cell life, compartmentalization and mechanisms allowing their maintenance despite continuous crosstalk among different organelles have been deeply investigated over the past years. Here, we review the multiple functions exerted by the endosomal sorting complex required for transport (ESCRT) machinery in driving membrane remodeling and fission, as well as in repairing physiological and pathological membrane damages. In this way, ESCRT machinery enables different fundamental cellular processes, such as cell cytokinesis, biogenesis of organelles and vesicles, maintenance of nuclear–cytoplasmic compartmentalization, endolysosomal activity. Furthermore, we discuss some examples of how viruses, as obligate intracellular parasites, have evolved to hijack the ESCRT machinery or part of it to execute/optimize their replication cycle/infection. A special emphasis is given to the herpes simplex virus type 1 (HSV-1) interaction with the ESCRT proteins, considering the peculiarities of this interplay and the need for HSV-1 to cross both the nuclear-cytoplasmic and the cytoplasmic-extracellular environment compartmentalization to egress from infected cells. Citation: Calistri, A.; Reale, A.; Palù, Keywords: ESCRT; viruses; cellular membranes; extracellular vesicles; HSV-1 G.; Parolin, C.
    [Show full text]
  • Molecular Mechanism for the Subversion of the Retromer Coat By
    Molecular mechanism for the subversion of the PNAS PLUS retromer coat by the Legionella effector RidL Miguel Romano-Morenoa, Adriana L. Rojasa, Chad D. Williamsonb, David C. Gershlickb, María Lucasa, Michail N. Isupovc, Juan S. Bonifacinob, Matthias P. Machnerd,1, and Aitor Hierroa,e,1 aStructural Biology Unit, Centro de Investigación Cooperativa en Biociencias, 48160 Derio, Spain; bCell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; cThe Henry Wellcome Building for Biocatalysis, Biosciences, University of Exeter, Exeter EX4 4SB, United Kingdom; dDivision of Molecular and Cellular Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; and eIKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain Edited by Ralph R. Isberg, Howard Hughes Medical Institute and Tufts University School of Medicine, Boston, MA, and approved November 13, 2017 (received for review August 30, 2017) Microbial pathogens employ sophisticated virulence strategies to VAMP7 together with several Rab GTPases that function along cause infections in humans. The intracellular pathogen Legionella distinct trafficking pathways (18), and the Tre-2/Bub2/Cdc16 pneumophila encodes RidL to hijack the host scaffold protein domain family member 5 (TBC1D5), a GTPase-activating pro- VPS29, a component of retromer and retriever complexes critical for tein (GAP) that causes Rab7 inactivation and redistribution to endosomal cargo recycling. Here, we determined the crystal structure the cytosol (14). of L. pneumophila RidL in complex with the human VPS29–VPS35 Recent biochemical and structural characterization of single retromer subcomplex. A hairpin loop protruding from RidL inserts subunits and subcomplexes from retromer have provided insights into a conserved pocket on VPS29 that is also used by cellular ligands, into its modular architecture and mechanisms of action.
    [Show full text]
  • Genetic, Structural and Clinical Analysis of Spastic Paraplegia 4
    medRxiv preprint doi: https://doi.org/10.1101/2021.07.20.21259482; this version posted July 20, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Genetic, structural and clinical analysis of spastic paraplegia 4 Parizad Varghaei1,2, MD, Mehrdad A Estiar2,3, MSc, Setareh Ashtiani4, MSc, Simon Veyron5, PhD, Kheireddin Mufti2,3, MSc, Etienne Leveille6, MD, Eric Yu2,3, BSc, Dan Spiegelman, MSc2, Marie-France Rioux7, MD, Grace Yoon8, MD, Mark Tarnopolsky9, MD, PhD, Kym M. Boycott10, MD, Nicolas Dupre11,12, MD, MSc, Oksana Suchowersky4,13, MD, Jean-François Trempe5,PhD, Guy A. Rouleau2,3,14, MD, PhD, Ziv Gan-Or2,3,14, MD, PhD 1. Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada 2. The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Quebec, Canada 3. Department of Human Genetics, McGill University, Montréal, Québec, Canada 4. Alberta Children’s Hospital, Medical Genetics, Calgary, Alberta, Canada 5. Department of Pharmacology & Therapeutics and Centre de Recherche en Biologie Structurale - FRQS, McGill University, Montréal, Canada 6. Faculty of Medicine, McGill University, Montreal, QC, Canada 7. Department of Neurology, Université de Sherbrooke, Sherbrooke, Québec, Canada. 8. Divisions of Neurology and Clinical and Metabolic Genetics, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada 9. Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada 10. Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada 11.
    [Show full text]
  • APP) Traffics from the Cell PNAS PLUS Surface Via Endosomes for Amyloid Β (Aβ) Production in the Trans-Golgi Network
    Amyloid precursor protein (APP) traffics from the cell PNAS PLUS surface via endosomes for amyloid β (Aβ) production in the trans-Golgi network Regina Wai-Yan Choya,b, Zhiliang Chenga,b, and Randy Schekmana,b,1 aDepartment of Molecular and Cell Biology and bHoward Hughes Medical Institute, University of California, Berkeley, CA 94720 Contributed by Randy Schekman, May 23, 2012 (sent for review January 14, 2012) Amyloid precursor protein (APP) is processed sequentially by the predominantly in early endosomes (12, 13). Hence, converging β-site APP cleaving enzyme and γ-secretase to generate amyloid β evidence confirmed the importance of the endocytic pathway in (Aβ) peptides, one of the hallmarks of Alzheimer’s disease. The the regulation of Aβ production. To date, there has been limited intracellular location of Aβ production—endosomes or the trans- detailed analysis dissecting the different downstream steps fol- Golgi network (TGN)—remains uncertain. We investigated the role lowing endocytosis to reveal the actual location in which Aβ is of different postendocytic trafficking events in Aβ40 production produced. Potential sites include early or late endosomes or the using an RNAi approach. Depletion of Hrs and Tsg101, acting early multivesicular body (MVB) involved in sorting transmembrane in the multivesicular body pathway, retained APP in early endo- proteins for degradation in the lysosome, as well as along the somes and reduced Aβ40 production. Conversely, depletion of retrograde pathway that mediates the recycling of endosomal CHMP6 and VPS4, acting late in the pathway, rerouted endosomal proteins to the TGN. APP to the TGN for enhanced APP processing. We found that We investigated the importance of different postendocytic VPS35 (retromer)-mediated APP recycling to the TGN was required trafficking steps in the production of Aβ40 by using an RNAi for efficient Aβ40 production.
    [Show full text]
  • Delivering of Proteins to the Plant Vacuole—An Update
    Int. J. Mol. Sci. 2014, 15, 7611-7623; doi:10.3390/ijms15057611 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Review Delivering of Proteins to the Plant Vacuole—An Update Cláudia Pereira 1,†, Susana Pereira 2,†,* and José Pissarra 2 1 Institute for Molecular and Cell Biology (IBMC), University of Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal; E-Mail: [email protected] 2 Department of Biology, Faculty of Sciences, University of Porto and Centre for Biodiversity, Functional and Integrative Genomics, Rua do Campo Alegre, s/n, FC4, 4169-007 Porto, Portugal; E-Mail: [email protected] † These authors contributed equally to this work. * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +351-220-402-000; Fax: +351-220-402-709. Received: 28 February 2014; in revised form: 21 April 2014 / Accepted: 22 April 2014 / Published: 5 May 2014 Abstract: Trafficking of soluble cargo to the vacuole is far from being a closed issue as it can occur by different routes and involve different intermediates. The textbook view of proteins being sorted at the post-Golgi level to the lytic vacuole via the pre-vacuole or to the protein storage vacuole mediated by dense vesicles is now challenged as novel routes are being disclosed and vacuoles with intermediate characteristics described. The identification of Vacuolar Sorting Determinants is a key signature to understand protein trafficking to the vacuole. Despite the long established vacuolar signals, some others have been described in the last few years, with different properties that can be specific for some cells or some types of vacuoles.
    [Show full text]
  • Actin, Microtubule, Septin and ESCRT Filament Remodeling During Late Steps of Cytokinesis Cyril Addi, Jian Bai, Arnaud Echard
    Actin, microtubule, septin and ESCRT filament remodeling during late steps of cytokinesis Cyril Addi, Jian Bai, Arnaud Echard To cite this version: Cyril Addi, Jian Bai, Arnaud Echard. Actin, microtubule, septin and ESCRT filament remodel- ing during late steps of cytokinesis. Current Opinion in Cell Biology, Elsevier, 2018, 50, pp.27-34. 10.1016/j.ceb.2018.01.007. hal-02114062 HAL Id: hal-02114062 https://hal.archives-ouvertes.fr/hal-02114062 Submitted on 29 Apr 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution - NonCommercial| 4.0 International License Actin, microtubule, septin and ESCRT filament remodeling during late steps of cytokinesis Cyril Addi1,2,3,#, Jian Bai1,2,3,# and Arnaud Echard1,2 1 Membrane Traffic and Cell Division Lab, Cell Biology and Infection department Institut Pasteur, 25–28 rue du Dr Roux, 75724 Paris cedex 15, France 2 Centre National de la Recherche Scientifique CNRS UMR3691, 75015 Paris, France 3 Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06, Institut de formation doctorale, 75252 Paris, France # equal contribution, alphabetical order correspondence: [email protected] 1 ABSTRACT Cytokinesis is the process by which a mother cell is physically cleaved into two daughter cells.
    [Show full text]
  • Hereditary Spastic Paraplegia: from Genes, Cells and Networks to Novel Pathways for Drug Discovery
    brain sciences Review Hereditary Spastic Paraplegia: From Genes, Cells and Networks to Novel Pathways for Drug Discovery Alan Mackay-Sim Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia; a.mackay-sim@griffith.edu.au Abstract: Hereditary spastic paraplegia (HSP) is a diverse group of Mendelian genetic disorders affect- ing the upper motor neurons, specifically degeneration of their distal axons in the corticospinal tract. Currently, there are 80 genes or genomic loci (genomic regions for which the causative gene has not been identified) associated with HSP diagnosis. HSP is therefore genetically very heterogeneous. Finding treatments for the HSPs is a daunting task: a rare disease made rarer by so many causative genes and many potential mutations in those genes in individual patients. Personalized medicine through genetic correction may be possible, but impractical as a generalized treatment strategy. The ideal treatments would be small molecules that are effective for people with different causative mutations. This requires identification of disease-associated cell dysfunctions shared across geno- types despite the large number of HSP genes that suggest a wide diversity of molecular and cellular mechanisms. This review highlights the shared dysfunctional phenotypes in patient-derived cells from patients with different causative mutations and uses bioinformatic analyses of the HSP genes to identify novel cell functions as potential targets for future drug treatments for multiple genotypes. Keywords: neurodegeneration; motor neuron disease; spastic paraplegia; endoplasmic reticulum; Citation: Mackay-Sim, A. Hereditary protein-protein interaction network Spastic Paraplegia: From Genes, Cells and Networks to Novel Pathways for Drug Discovery. Brain Sci. 2021, 11, 403.
    [Show full text]