ID UBQL4_HUMAN Reviewed; 601 AA. AC Q9NRR5; A6ND44; B2RAY7; Q5VYA0; Q5VYA1; Q9BR98; Q9UHX4; DT 15-MAR-2004, integrated into UniProtKB/Swiss-Prot. DT 15-MAR-2004, sequence version 2. DT 27-MAR-2024, entry version 189. DE RecName: Full=Ubiquilin-4 {ECO:0000305}; DE AltName: Full=Ataxin-1 interacting ubiquitin-like protein {ECO:0000303|PubMed:11001934}; DE Short=A1Up {ECO:0000303|PubMed:11001934}; DE AltName: Full=Ataxin-1 ubiquitin-like-interacting protein A1U; DE AltName: Full=Connexin43-interacting protein of 75 kDa {ECO:0000250|UniProtKB:Q99NB8}; DE Short=CIP75 {ECO:0000250|UniProtKB:Q99NB8}; GN Name=UBQLN4 {ECO:0000303|PubMed:27113755, ECO:0000312|HGNC:HGNC:1237}; GN Synonyms=C1orf6 {ECO:0000312|HGNC:HGNC:1237}, CIP75 GN {ECO:0000250|UniProtKB:Q99NB8}, UBIN {ECO:0000303|PubMed:29666234}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBCELLULAR LOCATION, INTERACTION RP WITH ATXN1/SCA1, AND TISSUE SPECIFICITY. RC TISSUE=Brain; RX PubMed=11001934; DOI=10.1093/oxfordjournals.hmg.a018922; RA Davidson J.D., Riley B., Burright E.N., Duvick L.A., Zoghbi H.Y., Orr H.T.; RT "Identification and characterization of an ataxin-1-interacting protein: RT A1Up, a ubiquitin-like nuclear protein."; RL Hum. Mol. Genet. 9:2305-2312(2000). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT RP MET-495. RC TISSUE=Brain; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain, Colon, and PNS; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] OF 161-601 (ISOFORM 1), AND VARIANT MET-495. RX PubMed=10575211; DOI=10.1159/000015344; RA Fogli A., Giglio S., Lo Nigro C., Zollo M., Viggiano L., Rocchi M., RA Archidiacono N., Zuffardi O., Carrozzo R.; RT "Identification of two paralogous regions mapping to the short and long RT arms of human chromosome 2 comprising LIS1 pseudogenes."; RL Cytogenet. Cell Genet. 86:225-232(1999). RN [6] RP FUNCTION, INTERACTION WITH UBIQUITIN; ATXN1 AND PSMD4, SUBUNIT, SUBCELLULAR RP LOCATION, AND UBIQUITINATION. RX PubMed=15280365; DOI=10.1074/jbc.m406284200; RA Riley B.E., Xu Y., Zoghbi H.Y., Orr H.T.; RT "The effects of the polyglutamine repeat protein ataxin-1 on the UbL-UBA RT protein A1Up."; RL J. Biol. Chem. 279:42290-42301(2004). RN [7] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Embryonic kidney; RX PubMed=17525332; DOI=10.1126/science.1140321; RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., RA Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., RA Gygi S.P., Elledge S.J.; RT "ATM and ATR substrate analysis reveals extensive protein networks RT responsive to DNA damage."; RL Science 316:1160-1166(2007). RN [8] RP INTERACTION WITH HERPUD1. RX PubMed=18307982; DOI=10.1016/j.bbrc.2008.02.086; RA Kim T.Y., Kim E., Yoon S.K., Yoon J.B.; RT "Herp enhances ER-associated protein degradation by recruiting RT ubiquilins."; RL Biochem. Biophys. Res. Commun. 369:741-746(2008). RN [9] RP INTERACTION WITH MUMPS VIRUS PROTEIN SH (MICROBIAL INFECTION). RX PubMed=20702650; DOI=10.1099/vir.0.024638-0; RA Woznik M., Roedner C., Lemon K., Rima B., Mankertz A., Finsterbusch T.; RT "Mumps virus small hydrophobic protein targets ataxin-1 ubiquitin-like RT interacting protein (ubiquilin 4)."; RL J. Gen. Virol. 91:2773-2781(2010). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-98, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION, SUBCELLULAR LOCATION, RP INTERACTION WITH UBQLN1; UBQLN2 AND MAP1LC3A/B/C, AND MUTAGENESIS OF RP ILE-55. RX PubMed=23459205; DOI=10.1038/embor.2013.22; RA Lee D.Y., Arnott D., Brown E.J.; RT "Ubiquilin4 is an adaptor protein that recruits Ubiquilin1 to the autophagy RT machinery."; RL EMBO Rep. 14:373-381(2013). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-287, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [14] RP REVIEW. RX PubMed=24674348; DOI=10.1186/1471-2148-14-63; RA Marin I.; RT "The ubiquilin gene family: evolutionary patterns and functional RT insights."; RL BMC Evol. Biol. 14:63-63(2014). RN [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [16] RP FUNCTION, AND INTERACTION WITH BAG6. RX PubMed=27113755; DOI=10.15252/embr.201541402; RA Suzuki R., Kawahara H.; RT "UBQLN4 recognizes mislocalized transmembrane domain proteins and targets RT these to proteasomal degradation."; RL EMBO Rep. 17:842-857(2016). RN [17] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-23 AND LYS-62, AND IDENTIFICATION RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). RN [18] RP INVOLVEMENT IN ALS, VARIANT ALS ALA-90, AND CHARACTERIZATION OF VARIANT ALS RP ALA-90. RX PubMed=28463112; DOI=10.7554/elife.25453; RA Edens B.M., Yan J., Miller N., Deng H.X., Siddique T., Ma Y.C.; RT "A novel ALS-associated variant in UBQLN4 regulates motor axon RT morphogenesis."; RL Elife 6:0-0(2017). RN [19] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH DESI1. RX PubMed=29666234; DOI=10.1073/pnas.1711017115; RA Hirayama S., Sugihara M., Morito D., Iemura S.I., Natsume T., Murata S., RA Nagata K.; RT "Nuclear export of ubiquitinated proteins via the UBIN-POST system."; RL Proc. Natl. Acad. Sci. U.S.A. 115:E4199-E4208(2018). RN [20] RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH MRE11, INDUCTION, RP PHOSPHORYLATION AT SER-144 AND SER-318, MUTAGENESIS OF SER-318, INVOLVEMENT RP IN UBDS, AND VARIANT UBDS 326-ARG--SER-601 DEL. RX PubMed=30612738; DOI=10.1016/j.cell.2018.11.024; RA Jachimowicz R.D., Beleggia F., Isensee J., Velpula B.B., Goergens J., RA Bustos M.A., Doll M.A., Shenoy A., Checa-Rodriguez C., Wiederstein J.L., RA Baranes-Bachar K., Bartenhagen C., Hertwig F., Teper N., Nishi T., RA Schmitt A., Distelmaier F., Luedecke H.J., Albrecht B., Krueger M., RA Schumacher B., Geiger T., Hoon D.S.B., Huertas P., Fischer M., Hucho T., RA Peifer M., Ziv Y., Reinhardt H.C., Wieczorek D., Shiloh Y.; RT "UBQLN4 represses homologous recombination and is overexpressed in RT aggressive tumors."; RL Cell 0:0-0(2019). RN [21] RP INTERACTION WITH BCL2A1 AND BCL2L10, SUBCELLULAR LOCATION, PHOSPHORYLATION RP AT SER-318, AND MUTAGENESIS OF SER-318. RX PubMed=34245648; DOI=10.1002/1878-0261.13058; RA Liu F., Pan R., Ding H., Gu L., Yang Y., Li C., Xu Y., Hu R., Chen H., RA Zhang X., Nie Y.; RT "UBQLN4 is an ATM substrate that stabilizes the anti-apoptotic proteins RT BCL2A1 and BCL2L10 in mesothelioma."; RL Mol. Oncol. 15:3738-3752(2021). CC -!- FUNCTION: Regulator of protein degradation that mediates the CC proteasomal targeting of misfolded, mislocalized or accumulated CC proteins (PubMed:15280365, PubMed:27113755, PubMed:29666234, CC PubMed:30612738). Acts by binding polyubiquitin chains of target CC proteins via its UBA domain and by interacting with subunits of the CC proteasome via its ubiquitin-like domain (PubMed:15280365, CC PubMed:27113755, PubMed:30612738). Key regulator of DNA repair that CC represses homologous recombination repair: in response to DNA damage, CC recruited to sites of DNA damage following phosphorylation by ATM and CC acts by binding and removing ubiquitinated MRE11 from damaged CC chromatin, leading to MRE11 degradation by the proteasome CC (PubMed:30612738). MRE11 degradation prevents homologous recombination CC repair, redirecting double-strand break repair toward non-homologous CC end joining (NHEJ) (PubMed:30612738). Specifically recognizes and binds CC mislocalized transmembrane-containing proteins and targets them to CC proteasomal degradation (PubMed:27113755). Collaborates with DESI1/POST CC in the export of ubiquitinated proteins from the nucleus to the CC cytoplasm (PubMed:29666234). Also plays a role in the regulation of the CC proteasomal degradation of non-ubiquitinated GJA1 (By similarity). Acts CC as an adapter protein that recruits UBQLN1 to the autophagy machinery CC (PubMed:23459205). Mediates the association of UBQLN1 with CC autophagosomes and the autophagy-related protein LC3 (MAP1LC3A/B/C) and CC may assist in the maturation of autophagosomes to autolysosomes by CC mediating autophagosome-lysosome fusion (PubMed:23459205). CC {ECO:0000250|UniProtKB:Q99NB8, ECO:0000269|PubMed:15280365, CC ECO:0000269|PubMed:23459205, ECO:0000269|PubMed:27113755, CC ECO:0000269|PubMed:29666234, ECO:0000269|PubMed:30612738}. CC -!- SUBUNIT: Homooligomer (PubMed:15280365, PubMed:30612738). Binds signal CC sequences of proteins that are targeted to the endoplasmic reticulum CC (By similarity). Interacts (via UBA domain) with GJA1 (not CC ubiquitinated) and with ubiquitin; both compete for the same binding CC site (By similarity). Interacts (via UBA domain) with ubiquitin and CC with polyubiquitin chains (By similarity). Interacts (via ubiquitin- CC like domain) with PSMD2 and PSMD4, regulatory subunits of the 26S CC proteasome (PubMed:15280365). Interacts with ATXN1/SCA1; interaction CC with ATXN1 inhibits polyubiquitination of UBQLN4 and interferes with CC PSMD4 binding (PubMed:11001934, PubMed:15280365). Interacts with CC HERPUD1 (PubMed:18307982). Interacts (via ubiquitin-like domain) with CC UBQLN1 (via UBA domain) (PubMed:23459205). Interacts with UBQLN2 CC (PubMed:23459205). Interacts (via STI1 1 and 2 domains) with CC MAP1LC3A/B/C (PubMed:23459205). Interacts with BAG6 (PubMed:27113755). CC Interacts with MRE11 (when ubiquitinated); interaction with CC ubiquitinated MRE11 leads to MRE11 removal from chromatin CC (PubMed:30612738). Interacts with DESI1/POST; leading to nuclear export CC (PubMed:29666234). Interacts with BCL2A1 and BCL2L10 (PubMed:34245648). CC {ECO:0000250|UniProtKB:Q99NB8, ECO:0000269|PubMed:11001934, CC ECO:0000269|PubMed:15280365, ECO:0000269|PubMed:18307982, CC ECO:0000269|PubMed:23459205, ECO:0000269|PubMed:27113755, CC ECO:0000269|PubMed:29666234, ECO:0000269|PubMed:30612738, CC ECO:0000269|PubMed:34245648}. CC -!- SUBUNIT: (Microbial infection) Interacts with Mumps virus protein SH. CC {ECO:0000269|PubMed:20702650}. CC -!- INTERACTION: CC Q9NRR5; P54253: ATXN1; NbExp=6; IntAct=EBI-711226, EBI-930964; CC Q9NRR5; P26885: FKBP2; NbExp=2; IntAct=EBI-711226, EBI-719873; CC Q9NRR5; P48723: HSPA13; NbExp=3; IntAct=EBI-711226, EBI-750892; CC Q9NRR5; Q9H492: MAP1LC3A; NbExp=3; IntAct=EBI-711226, EBI-720768; CC Q9NRR5; P55198: MLLT6; NbExp=2; IntAct=EBI-711226, EBI-740216; CC Q9NRR5; Q9NR12: PDLIM7; NbExp=2; IntAct=EBI-711226, EBI-350517; CC Q9NRR5; Q9Y5P3: RAI2; NbExp=3; IntAct=EBI-711226, EBI-746228; CC Q9NRR5; Q13049: TRIM32; NbExp=3; IntAct=EBI-711226, EBI-742790; CC Q9NRR5; Q9UMX0: UBQLN1; NbExp=8; IntAct=EBI-711226, EBI-741480; CC Q9NRR5; Q9NRR5: UBQLN4; NbExp=3; IntAct=EBI-711226, EBI-711226; CC Q9NRR5; O95201: ZNF205; NbExp=2; IntAct=EBI-711226, EBI-747343; CC Q9NRR5; P08050: Gja1; Xeno; NbExp=2; IntAct=EBI-711226, EBI-476947; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:11001934, CC ECO:0000269|PubMed:15280365, ECO:0000269|PubMed:29666234, CC ECO:0000269|PubMed:30612738, ECO:0000269|PubMed:34245648}. Cytoplasm CC {ECO:0000269|PubMed:29666234, ECO:0000269|PubMed:30612738, CC ECO:0000269|PubMed:34245648}. Chromosome {ECO:0000269|PubMed:30612738}. CC Endoplasmic reticulum {ECO:0000250|UniProtKB:Q99NB8}. Cytoplasm, CC perinuclear region {ECO:0000250|UniProtKB:Q99NB8}. Cytoplasmic vesicle, CC autophagosome {ECO:0000269|PubMed:23459205}. Note=Colocalizes with the CC proteasome, both in nucleus and cytoplasm (PubMed:15280365). Exported CC from the nucleus following interaction with DESI1/POST CC (PubMed:29666234). In response to DNA damage and phosphorylation at CC Ser-318 by ATM, localizes to the nucleus and is recruited to sites of CC DNA damage (PubMed:30612738). {ECO:0000269|PubMed:15280365, CC ECO:0000269|PubMed:29666234, ECO:0000269|PubMed:30612738}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9NRR5-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9NRR5-2; Sequence=VSP_041187, VSP_041188; CC -!- TISSUE SPECIFICITY: Highly expressed in pancreas, kidney, skeletal CC muscle, heart and throughout the brain, and at lower levels in CC placenta, lung and liver. {ECO:0000269|PubMed:11001934}. CC -!- INDUCTION: Up-regulated in aggressive tumors: expression is CC significantly increased in stage 3 and 4 neuroblastomas, compared to CC stage 1 disease. {ECO:0000269|PubMed:30612738}. CC -!- PTM: Phosphorylated by ATM at Ser-318 in response to DNA damage, CC leading to localization in the nucleus and recruitment to sites of DNA CC damage. {ECO:0000269|PubMed:30612738, ECO:0000269|PubMed:34245648}. CC -!- PTM: Ubiquitinated; this does not lead to proteasomal degradation CC (PubMed:15280365). May undergo both 'Lys-48'- and 'Lys-63'-linked CC polyubiquitination (PubMed:15280365). {ECO:0000269|PubMed:15280365}. CC -!- DISEASE: Amyotrophic lateral sclerosis (ALS) [MIM:105400]: A CC neurodegenerative disorder affecting upper motor neurons in the brain CC and lower motor neurons in the brain stem and spinal cord, resulting in CC fatal paralysis. Sensory abnormalities are absent. The pathologic CC hallmarks of the disease include pallor of the corticospinal tract due CC to loss of motor neurons, presence of ubiquitin-positive inclusions CC within surviving motor neurons, and deposition of pathologic CC aggregates. The etiology of amyotrophic lateral sclerosis is likely to CC be multifactorial, involving both genetic and environmental factors. CC The disease is inherited in 5-10% of the cases. CC {ECO:0000269|PubMed:28463112}. Note=Disease susceptibility is CC associated with variants affecting the gene represented in this entry. CC -!- DISEASE: Note=Defects in UBQLN4 are the cause of the UBQLN4 deficiency CC syndrome (UBDS) (PubMed:30612738). Patients display intellectual CC impairment, growth retardation, microcephaly, facial dysmorphism, CC hearing loss, ataxia and anemia (PubMed:30612738). Cells display CC genomic instability characterized by hypersensitivity to genotoxic CC agents, leading to enhanced apoptotic cell death in response to DNA CC damage (PubMed:30612738). {ECO:0000269|PubMed:30612738}. CC -!- MISCELLANEOUS: May be a potential prognostic marker in cancer patients. CC {ECO:0000269|PubMed:34245648}. CC -!- SEQUENCE CAUTION: CC Sequence=AAF19084.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH06410.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF188240; AAF80171.1; -; mRNA. DR EMBL; AK098368; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AK314413; BAG37034.1; -; mRNA. DR EMBL; AL355388; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC006410; AAH06410.1; ALT_INIT; mRNA. DR EMBL; BC018403; AAH18403.1; -; mRNA. DR EMBL; BC063841; AAH63841.1; -; mRNA. DR EMBL; AF113544; AAF19084.1; ALT_INIT; mRNA. DR CCDS; CCDS1127.1; -. [Q9NRR5-1] DR RefSeq; NP_001291271.1; NM_001304342.1. DR RefSeq; NP_064516.2; NM_020131.4. [Q9NRR5-1] DR AlphaFoldDB; Q9NRR5; -. DR BMRB; Q9NRR5; -. DR SASBDB; Q9NRR5; -. DR SMR; Q9NRR5; -. DR BioGRID; 121223; 264. DR IntAct; Q9NRR5; 166. DR MINT; Q9NRR5; -. DR STRING; 9606.ENSP00000357292; -. DR TCDB; 8.A.52.1.1; the ubiquitin-related protein degradation (upd) family. DR GlyCosmos; Q9NRR5; 2 sites, 2 glycans. DR GlyGen; Q9NRR5; 2 sites, 2 O-linked glycans (2 sites). DR iPTMnet; Q9NRR5; -. DR PhosphoSitePlus; Q9NRR5; -. DR BioMuta; UBQLN4; -. DR DMDM; 45476982; -. DR EPD; Q9NRR5; -. DR jPOST; Q9NRR5; -. DR MassIVE; Q9NRR5; -. DR MaxQB; Q9NRR5; -. DR PaxDb; 9606-ENSP00000357292; -. DR PeptideAtlas; Q9NRR5; -. DR ProteomicsDB; 82412; -. [Q9NRR5-1] DR ProteomicsDB; 82413; -. [Q9NRR5-2] DR Pumba; Q9NRR5; -. DR TopDownProteomics; Q9NRR5-2; -. [Q9NRR5-2] DR Antibodypedia; 34204; 139 antibodies from 26 providers. DR DNASU; 56893; -. DR Ensembl; ENST00000368309.4; ENSP00000357292.3; ENSG00000160803.8. [Q9NRR5-1] DR GeneID; 56893; -. DR KEGG; hsa:56893; -. DR MANE-Select; ENST00000368309.4; ENSP00000357292.3; NM_020131.5; NP_064516.2. DR UCSC; uc001fna.4; human. [Q9NRR5-1] DR AGR; HGNC:1237; -. DR CTD; 56893; -. DR DisGeNET; 56893; -. DR GeneCards; UBQLN4; -. DR HGNC; HGNC:1237; UBQLN4. DR HPA; ENSG00000160803; Low tissue specificity. DR MalaCards; UBQLN4; -. DR MIM; 105400; phenotype. DR MIM; 605440; gene. DR neXtProt; NX_Q9NRR5; -. DR OpenTargets; ENSG00000160803; -. DR PharmGKB; PA25619; -. DR VEuPathDB; HostDB:ENSG00000160803; -. DR eggNOG; KOG0010; Eukaryota. DR GeneTree; ENSGT00940000155620; -. DR HOGENOM; CLU_024293_4_0_1; -. DR InParanoid; Q9NRR5; -. DR OMA; NRTGDQP; -. DR OrthoDB; 5491123at2759; -. DR PhylomeDB; Q9NRR5; -. DR TreeFam; TF314412; -. DR PathwayCommons; Q9NRR5; -. DR SignaLink; Q9NRR5; -. DR SIGNOR; Q9NRR5; -. DR BioGRID-ORCS; 56893; 195 hits in 1125 CRISPR screens. DR ChiTaRS; UBQLN4; human. DR GenomeRNAi; 56893; -. DR Pharos; Q9NRR5; Tbio. DR PRO; PR:Q9NRR5; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q9NRR5; Protein. DR Bgee; ENSG00000160803; Expressed in cortical plate and 172 other cell types or tissues. DR GO; GO:0005776; C:autophagosome; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:UniProtKB-KW. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; ISS:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB. DR GO; GO:0090734; C:site of DNA damage; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0036435; F:K48-linked polyubiquitin modification-dependent protein binding; IDA:UniProtKB. DR GO; GO:0031593; F:polyubiquitin modification-dependent protein binding; IDA:UniProtKB. DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW. DR GO; GO:0006974; P:DNA damage response; IDA:UniProtKB. DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW. DR GO; GO:1901097; P:negative regulation of autophagosome maturation; IMP:UniProtKB. DR GO; GO:2000042; P:negative regulation of double-strand break repair via homologous recombination; IDA:UniProtKB. DR GO; GO:0032434; P:regulation of proteasomal ubiquitin-dependent protein catabolic process; IDA:UniProtKB. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IBA:GO_Central. DR CDD; cd14399; UBA_PLICs; 1. DR CDD; cd01808; Ubl_PLICs; 1. DR Gene3D; 1.10.260.100; -; 2. DR Gene3D; 1.10.8.10; DNA helicase RuvA subunit, C-terminal domain; 1. DR InterPro; IPR006636; STI1_HS-bd. DR InterPro; IPR015940; UBA. DR InterPro; IPR009060; UBA-like_sf. DR InterPro; IPR015496; Ubiquilin. DR InterPro; IPR000626; Ubiquitin-like_dom. DR InterPro; IPR029071; Ubiquitin-like_domsf. DR PANTHER; PTHR10677; UBIQUILIN; 1. DR PANTHER; PTHR10677:SF21; UBIQUILIN-4; 1. DR Pfam; PF00627; UBA; 1. DR Pfam; PF00240; ubiquitin; 1. DR SMART; SM00727; STI1; 4. DR SMART; SM00165; UBA; 1. DR SMART; SM00213; UBQ; 1. DR SUPFAM; SSF46934; UBA-like; 1. DR SUPFAM; SSF54236; Ubiquitin-like; 1. DR PROSITE; PS50030; UBA; 1. DR PROSITE; PS50053; UBIQUITIN_2; 1. DR Genevisible; Q9NRR5; HS. PE 1: Evidence at protein level; KW Alternative splicing; Amyotrophic lateral sclerosis; Autophagy; Chromosome; KW Cytoplasm; Cytoplasmic vesicle; Disease variant; DNA damage; DNA repair; KW Endoplasmic reticulum; Isopeptide bond; Neurodegeneration; Nucleus; KW Phosphoprotein; Reference proteome; Ubl conjugation. FT CHAIN 1..601 FT /note="Ubiquilin-4" FT /id="PRO_0000211015" FT DOMAIN 13..87 FT /note="Ubiquitin-like" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00214" FT DOMAIN 192..229 FT /note="STI1 1" FT /evidence="ECO:0000255" FT DOMAIN 230..261 FT /note="STI1 2" FT /evidence="ECO:0000255" FT DOMAIN 393..440 FT /note="STI1 3" FT /evidence="ECO:0000255" FT DOMAIN 444..476 FT /note="STI1 4" FT /evidence="ECO:0000255" FT DOMAIN 553..598 FT /note="UBA" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00212" FT REGION 87..155 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 301..366 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 490..533 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 90..104 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 116..140 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 301..325 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 340..366 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 495..533 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 98 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 144 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:30612738" FT MOD_RES 287 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 318 FT /note="Phosphoserine; by ATM" FT /evidence="ECO:0000269|PubMed:30612738, FT ECO:0000269|PubMed:34245648" FT CROSSLNK 23 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT CROSSLNK 62 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT VAR_SEQ 93..226 FT /note="AATASSPSTPDPASAPSTTPASPATPAQPSTSGSASSDAGSGSRRSSGGGPS FT PGAGEGSPSATASILSGFGGILGLGSLGLGSANFMELQQQMQRQLMSNPEMLSQIMENP FT LVQDMMSNPDLMRHMIMANPQMQ -> PPAAPSLPAADAEPRVTLHPYQSPSHAGIAAD FT PAGTTDLADRGPWAGTQPWLLWDIPDPSTLSRQQRRVYARGPHFLTSHASHIFSNRGFQ FT RPAATHAADDPAFGWKWKLTGADARSEISAAAGAAQLHGLHQS (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_041187" FT VAR_SEQ 227..601 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_041188" FT VARIANT 90 FT /note="D -> A (in ALS; impaired proteasome efficiency FT leading to accumulation of CTNNB1; dbSNP:rs1465567777)" FT /evidence="ECO:0000269|PubMed:28463112" FT /id="VAR_081427" FT VARIANT 326..601 FT /note="Missing (found in patients with UBQLN4 deficiency FT syndrome (UBDS); likely pathogenic)" FT /evidence="ECO:0000269|PubMed:30612738" FT /id="VAR_081428" FT VARIANT 495 FT /note="I -> M (in dbSNP:rs2297792)" FT /evidence="ECO:0000269|PubMed:10575211, FT ECO:0000269|PubMed:14702039" FT /id="VAR_052685" FT MUTAGEN 55 FT /note="I->A: Loss of interaction with UBQLN1." FT MUTAGEN 318 FT /note="S->A: Abolishes phosphorylation by ATM in response FT to DNA damage and impaired ability to regulate DNA repair." FT /evidence="ECO:0000269|PubMed:30612738, FT ECO:0000269|PubMed:34245648" FT CONFLICT 188..189 FT /note="QL -> HV (in Ref. 1; AAF80171)" FT /evidence="ECO:0000305" FT CONFLICT 298 FT /note="R -> Q (in Ref. 1; AAF80171)" FT /evidence="ECO:0000305" SQ SEQUENCE 601 AA; 63853 MW; E57B9FFEF90793FE CRC64; MAEPSGAETR PPIRVTVKTP KDKEEIVICD RASVKEFKEE ISRRFKAQQD QLVLIFAGKI LKDGDTLNQH GIKDGLTVHL VIKTPQKAQD PAAATASSPS TPDPASAPST TPASPATPAQ PSTSGSASSD AGSGSRRSSG GGPSPGAGEG SPSATASILS GFGGILGLGS LGLGSANFME LQQQMQRQLM SNPEMLSQIM ENPLVQDMMS NPDLMRHMIM ANPQMQQLME RNPEISHMLN NPELMRQTME LARNPAMMQE MMRNQDRALS NLESIPGGYN ALRRMYTDIQ EPMFSAAREQ FGNNPFSSLA GNSDSSSSQP LRTENREPLP NPWSPSPPTS QAPGSGGEGT GGSGTSQVHP TVSNPFGINA ASLGSGMFNS PEMQALLQQI SENPQLMQNV ISAPYMRSMM QTLAQNPDFA AQMMVNVPLF AGNPQLQEQL RLQLPVFLQQ MQNPESLSIL TNPRAMQALL QIQQGLQTLQ TEAPGLVPSL GSFGISRTPA PSAGSNAGST PEAPTSSPAT PATSSPTGAS SAQQQLMQQM IQLLAGSGNS QVQTPEVRFQ QQLEQLNSMG FINREANLQA LIATGGDINA AIERLLGSQL S //