UBQL4_HUMAN
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 03-AUG-2022, entry version 180.
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},
GN CIP75 {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; 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};
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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 SMR; Q9NRR5; -.
DR BioGRID; 121223; 242.
DR IntAct; Q9NRR5; 165.
DR MINT; Q9NRR5; -.
DR STRING; 9606.ENSP00000357292; -.
DR TCDB; 8.A.52.1.1; the ubiquitin-related protein degradation (upd) family.
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; Q9NRR5; -.
DR PeptideAtlas; Q9NRR5; -.
DR PRIDE; Q9NRR5; -.
DR ProteomicsDB; 82412; -. [Q9NRR5-1]
DR ProteomicsDB; 82413; -. [Q9NRR5-2]
DR TopDownProteomics; Q9NRR5-2; -. [Q9NRR5-2]
DR Antibodypedia; 34204; 116 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 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; GVKMADQ; -.
DR OrthoDB; 1553668at2759; -.
DR PhylomeDB; Q9NRR5; -.
DR TreeFam; TF314412; -.
DR PathwayCommons; Q9NRR5; -.
DR SignaLink; Q9NRR5; -.
DR SIGNOR; Q9NRR5; -.
DR BioGRID-ORCS; 56893; 180 hits in 1045 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 170 other tissues.
DR Genevisible; Q9NRR5; HS.
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:cellular response to DNA damage stimulus; 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 InterPro; IPR006636; STI1_HS-bd.
DR InterPro; IPR015940; UBA.
DR InterPro; IPR009060; UBA-like_sf.
DR InterPro; IPR000626; Ubiquitin-like_dom.
DR InterPro; IPR029071; Ubiquitin-like_domsf.
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; SSF46934; 1.
DR SUPFAM; SSF54236; SSF54236; 1.
DR PROSITE; PS50030; UBA; 1.
DR PROSITE; PS50053; UBIQUITIN_2; 1.
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 (probable disease-associated variant found
FT in patients with UBQLN4 deficiency syndrome (UBDS))"
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
