BioPAX pathway converted from "ATXN3 family cleave Ub chains" in the Reactome database.LEFT-TO-RIGHTATXN3 family cleave Ub chainsAtaxin-3 (ATXN3) has an N-terminal Josephin domain (JD) that is conserved within a family of around 4 ubiquitin proteases. ATXN3, the best studied, can bind long chains of lysine-63 (K63)-linked and K48-linked poly-ubiquitin (poly-Ub), but its activity is highest for ubiquitin chains with at least four molecules of ubiquitin. It preferentially cleaves linkages between ubiquitin molecules linked through K63 rather than K48 (Winborn et al. 2008). In effect this trims longer polyubiquitin chains down to approximately four residues (Burnett et al. 2003). The other three human JD-containing proteins also have demonstrated deubiquitinase (DUB) activity (Tzvetkov & Breuer 2007). In vitro ATXN3 kinetics are slow when compared to other well-studied deubiquitinating enzymes (Nicastro et al. 2010) but become much faster when ATXN3 is activated by VCP (Laco et al. 2012). JOSD1 partially localizes to the plasma membrane (Seki et al. 2013).Authored: Jupe, Steve, 2015-04-16Reviewed: Meldal, Birgit, 2016-05-16Edited: Jupe, Steve, 2016-05-05K63polyUbK63-polyubiquitinLys-63 polyubiquitinReactome DB_ID: 450152cytosolGENE ONTOLOGYGO:0005829Reactome Database ID Release 75450152Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450152ReactomeR-HSA-4501522Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450152.2Reactomehttp://www.reactome.orgChEBI36080additional informationMIMI:0361H2OwaterReactome DB_ID: 29356water [ChEBI:15377]waterChEBICHEBI:15377Reactome Database ID Release 7529356Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29356ReactomeR-ALL-293565Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29356.5COMPOUNDC00001Short K63polyUbK63-polyubiquitinLys-63 polyubiquitinReactome DB_ID: 6783297Reactome Database ID Release 756783297Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6783297ReactomeR-HSA-67832973Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6783297.3ChEBI36080Converted from EntitySet in ReactomeK63-UbK63-ubiquitinReactome DB_ID: 450143Ub-63-RPS27AUb-63-RPS27A(1-76)K63 ubiquitin (RPS27A)Reactome DB_ID: 939248UniProt:P62979 RPS27ARPS27AUBA80UBCEP1SUBUNIT Ribosomal protein S27a is part of the 40S ribosomal subunit.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eS31 family.Homo sapiensNCBI Taxonomy9606UniProtP6297963EQUALubiquitinylated lysineMODMOD:011481EQUAL76EQUALReactome Database ID Release 75939248Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939248ReactomeR-HSA-9392481Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-939248.1Ub-63-UBA52Ub-63-UBA52(1-76)K63 ubiquitin (UBA52)Reactome DB_ID: 939169UniProt:P62987 UBA52UBA52UBCEP2SUBUNIT Ribosomal protein L40 is part of the 60S ribosomal subunit. Interacts with UBQLN1 (via UBA domain).MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eL40 family.UniProtP6298763EQUAL1EQUAL76EQUALReactome Database ID Release 75939169Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939169ReactomeR-HSA-9391691Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-939169.1Ub-63-UBBUb-63-UBB(1-76)K63 ubiquitin (UBB 1)Reactome DB_ID: 939224UniProt:P0CG47 UBBUBBSUBUNIT Interacts with SKP1-KMD2A and SKP1-KMD2B complexes.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS The mRNA encoding variant UBB(+1) is produced by an unknown mechanism involving the deletion of a GT dinucleotide in the close proximity of a GAGAG motif (PubMed:9422699). This variant mRNA is found in normal brain, but the encoded protein accumulates only in brain neurofibrillary tangles and neuritic plaques in Alzheimer disease and other tauopathies, as well as polyglutaminopathies (PubMed:14597671). UBB(+1) variant cannot be used for polyubiquitination, is not effectively degraded by the proteasome when ubiquitinated and ubiquitinated UBB(+1) is refractory to disassembly by deubiquitinating enzymes (DUBs). In healthy brain, UBB(+1) C-terminus can be cleaved by UCHL3 (PubMed:21762696).MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY Belongs to the ubiquitin family.UniProtP0CG4763EQUAL1EQUAL76EQUALReactome Database ID Release 75939224Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939224ReactomeR-HSA-9392241Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-939224.1Ub-139-UBB(77-152)K63 ubiquitin (UBB 2)Reactome DB_ID: 939235139EQUAL77EQUAL152EQUALReactome Database ID Release 75939235Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939235ReactomeR-HSA-9392351Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-939235.1Ub-215-UBB(153-228)K63 ubiquitin (UBB 3)Reactome DB_ID: 939168215EQUAL153EQUAL228EQUALReactome Database ID Release 75939168Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939168ReactomeR-HSA-9391681Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-939168.1Ub-63-UBCUb-63-UBC(1-76)K63 ubiquitin (UBC 1)Reactome DB_ID: 939176UniProt:P0CG48 UBCUBCMISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For the sake of clarity sequence features are annotated only for the first chain, and are not repeated for each of the following chains.SIMILARITY Belongs to the ubiquitin family.UniProtP0CG4863EQUAL1EQUAL76EQUALReactome Database ID Release 75939176Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939176ReactomeR-HSA-9391761Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-939176.1Ub-139-UBC(77-152)K63 ubiquitin (UBC 2)Reactome DB_ID: 939254139EQUAL77EQUAL152EQUALReactome Database ID Release 75939254Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939254ReactomeR-HSA-9392541Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-939254.1Ub-215-UBC(153-228)K63 ubiquitin (UBC 3)Reactome DB_ID: 939186215EQUAL153EQUAL228EQUALReactome Database ID Release 75939186Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939186ReactomeR-HSA-9391861Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-939186.1Ub-291-UBC(229-304)K63 ubiquitin (UBC 4)Reactome DB_ID: 939173291EQUAL229EQUAL304EQUALReactome Database ID Release 75939173Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939173ReactomeR-HSA-9391731Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-939173.1Ub-367-UBC(305-380)K63 ubiquitin (UBC 5)Reactome DB_ID: 939206367EQUAL305EQUAL380EQUALReactome Database ID Release 75939206Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939206ReactomeR-HSA-9392061Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-939206.1Ub-443-UBC(381-456)K63 ubiquitin (UBC 6)Reactome DB_ID: 939182443EQUAL381EQUAL456EQUALReactome Database ID Release 75939182Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939182ReactomeR-HSA-9391821Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-939182.1Ub-519-UBC(457-532)K63 ubiquitin (UBC 7)Reactome DB_ID: 939212519EQUAL457EQUAL532EQUALReactome Database ID Release 75939212Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939212ReactomeR-HSA-9392121Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-939212.1Ub-595-UBC(533-608)K63 ubiquitin (UBC 8)Reactome DB_ID: 939198595EQUAL533EQUAL608EQUALReactome Database ID Release 75939198Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939198ReactomeR-HSA-9391981Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-939198.1Ub-671-UBC(609-684)K63 ubiquitin (UBC 9)Reactome DB_ID: 939241671EQUAL609EQUAL684EQUALReactome Database ID Release 75939241Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939241ReactomeR-HSA-9392411Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-939241.1Reactome Database ID Release 75450143Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450143ReactomeR-HSA-4501431Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450143.1ACTIVATIONConverted from EntitySet in ReactomeATXN3,ATXN3L,JOSD1,JOSD2Reactome DB_ID: 5688839ATXN3Ataxin-3ATX3_HUMANReactome DB_ID: 5625607UniProt:P54252 ATXN3ATXN3ATX3MJDMJD1SCA3FUNCTION Deubiquitinating enzyme involved in protein homeostasis maintenance, transcription, cytoskeleton regulation, myogenesis and degradation of misfolded chaperone substrates (PubMed:12297501, PubMed:17696782, PubMed:23625928, PubMed:28445460, PubMed:16118278). Binds long polyubiquitin chains and trims them, while it has weak or no activity against chains of 4 or less ubiquitins (PubMed:17696782). Involved in degradation of misfolded chaperone substrates via its interaction with STUB1/CHIP: recruited to monoubiquitinated STUB1/CHIP, and restricts the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension (By similarity). Interacts with key regulators of transcription and represses transcription: acts as a histone-binding protein that regulates transcription (PubMed:12297501). Regulates autophagy via the deubiquitination of 'Lys-402' of BECN1 leading to the stabilization of BECN1 (PubMed:28445460).SUBUNIT Interacts with STUB1/CHIP (when monoubiquitinated) (By similarity). Interacts with DNA repair proteins RAD23A and RAD23B (PubMed:16020535, PubMed:30455355). Interacts with BECN1 (via its poly-Gln domain) (PubMed:28445460). Interacts with PRKN, UBR2, VCP and tubulin. Short isoform 1 interacts with CASP7 (PubMed:30455355).TISSUE SPECIFICITY Ubiquitous.DOMAIN The UIM domains bind ubiquitin and interact with various E3 ubiquitin-protein ligase, such as STUB1/CHIP. They are essential to limit the length of ubiquitin chains (By similarity).DOMAIN The poly-Gln domain is involved in the interaction with BECN1 and subsequent starvation-induced autophagy (PubMed:28445460).PTM Monoubiquitinated N-terminally by UBE2W, possibly leading to activate the deubiquitinating enzyme activity (PubMed:23696636).POLYMORPHISM The poly-Gln region of ATXN3 is highly polymorphic (14 to 41 repeats) in the normal population and is expanded to about 55-82 repeats in spinocerebellar ataxia 3 (SCA3) patients (PubMed:7874163, PubMed:9274833).UniProtP542521EQUAL364EQUALReactome Database ID Release 755625607Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5625607ReactomeR-HSA-56256072Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5625607.2ATXN3LPutative ataxin-3-like protein ecNumber3.4.19.12/ecNumberATX3L_HUMANReactome DB_ID: 5688758UniProt:Q9H3M9 ATXN3LATXN3LATX3LMJDLFUNCTION Deubiquitinating enzyme that cleaves both 'Lys-48'-linked and 'Lys-63'-linked poly-ubiquitin chains (in vitro).UniProtQ9H3M91EQUAL355EQUALReactome Database ID Release 755688758Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5688758ReactomeR-HSA-56887582Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5688758.2JOSD1Josephin-1 ecNumber3.4.19.12/ecNumberJOS1_HUMANReactome DB_ID: 5688784UniProt:Q15040 JOSD1JOSD1JSPH1KIAA0063FUNCTION Deubiquitinates monoubiquitinated probes (in vitro). When ubiquitinated, cleaves 'Lys-63'-linked and 'Lys-48'-linked poly-ubiquitin chains (in vitro), hence may act as a deubiquitinating enzyme. May increase macropinocytosis and suppress clathrin- and caveolae-mediated endocytosis. May enhance membrane dynamics and cell motility independently of its catalytic activity.SUBUNIT Interacts with beta-actin/ACTB.PTM Monoubiquitinated (By similarity). Ubiquitination activates deubiquitination activity in vitro.UniProtQ150401EQUAL202EQUALReactome Database ID Release 755688784Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5688784ReactomeR-HSA-56887842Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5688784.2JOSD2Josephin-2JOS2_HUMANReactome DB_ID: 5688775UniProt:Q8TAC2 JOSD2JOSD2SBBI54FUNCTION Cleaves 'Lys-63'-linked poly-ubiquitin chains, and with lesser efficiency 'Lys-48'-linked poly-ubiquitin chains (in vitro). May act as a deubiquitinating enzyme.UniProtQ8TAC21EQUAL188EQUALReactome Database ID Release 755688775Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5688775ReactomeR-HSA-56887752Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5688775.2Reactome Database ID Release 755688839Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5688839ReactomeR-HSA-56888392Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5688839.2GENE ONTOLOGYGO:0004843gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 755688828Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5688828Reactome Database ID Release 755688797Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5688797ReactomeR-HSA-56887972Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5688797.220865150Pubmed2010Understanding the role of the Josephin domain in the PolyUb binding and cleavage properties of ataxin-3Nicastro, GiuseppeTodi, Sokol VKaraca, EzgiBonvin, Alexandre M J JPaulson, Henry LPastore, AnnalisaPLoS ONE 5:e1243017696782Pubmed2007Josephin domain-containing proteins from a variety of species are active de-ubiquitination enzymesTzvetkov, NikolayBreuer, PeterBiol. Chem. 388:973-822970133Pubmed2012Valosin-containing protein (VCP/p97) is an activator of wild-type ataxin-3Laço, Mário NCortes, LuisaTravis, Sue MPaulson, Henry LRego, A CristinaPLoS ONE 7:e4356314559776Pubmed2003The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activityBurnett, BarringtonLi, FushengPittman, Randall NHum. Mol. Genet. 12:3195-20523625928Pubmed2013JosD1, a membrane-targeted deubiquitinating enzyme, is activated by ubiquitination and regulates membrane dynamics, cell motility, and endocytosisSeki, TakahiroGong, LijieWilliams, Aislinn JSakai, NorioTodi, Sokol VPaulson, Henry LJ. Biol. Chem. 288:17145-5518599482Pubmed2008The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chainsWinborn, Brett JTravis, Sue MTodi, Sokol VScaglione, K MatthewXu, PingWilliams, Aislinn JCohen, Robert EPeng, JunminPaulson, Henry LJ. Biol. Chem. 283:26436-43