OTUD4 (4q31.21)
Vaihtoehtoisesti
silmukoituneita transkriptivariantteja löydetään tästä
geenistä. Tätä lyhyttä proteiini-isoformia on havaittavissa vain
HIV-1 retroviruksella infektoituneissa soluissa. Geenillä on
synonyyminimiä HIN1, DUBA6, HSHIN1. Jo vuonna 1992 tutkijat
tekivät havainnon proteiinista, jota muodostui vain HIV1 viruksella
infektoituneista soluista. (”HIV-1 promotor insertion revealed by
selective detection of chimeric provirus-host-gene transcripts).
Pitemmässä variantissa on 1049 aminohappoa. Vaihtoehtoisnimi
proteiinille on HIV-1 viruksen indusoima proteiini HIN-1. Suositeltu
nimi on OTU-domeenin sisältävä proteiini 4. OTUD4 pidetään varsinaisesti K48
deubikitinaasina, mutta fosfoaktivoitu OTUD4 paljastaa sen latentin
K63-deubikitinaasipiirteen, joka säätelee MyD88:sta riippuvaa järjestelmää.
(MyD99 proteiini on tärkeänä adaptorina järjestelmässä, joka
tunnistaa soluun tulevia patogeenejä Tollin reseptoreilla).
https://www.researchgate.net/figure/Signal-transduction-downstream-of-MYD88-dependent-and-independent-pathways-Activation-of_fig1_264866332.
OTUD4 osallistuu
DNA:n alkylaatiovaurion korjaukseen toimimalla alustana tai
rekrytoijana toisille DUB-perheen jäsenille ( USP7/HAUSP ja USP9X),
jotka edistävät DNA:n alkylaatiovauriota korjaavien
demetylaasien (hAlkBH2 ja hAlkBH3) dealkyloivia toimia - kun ne
irrottavat DNA:n puriinista N1-asemaN ALKYYLIÄ tai pyrimidiinistä N3 -
aseman alkyylia.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475402/
(Laajemman käsityksen DNA:n korjaukseen osllistuvista DUB- entsyymeistä saa Springerlinkistä.
PubMed tietoa OTUD GEENISTÄ (4q31.12)
- https://www.ncbi.nlm.nih.gov/gene/54726
- Also known as HIN1; DUBA6; HSHIN1
- Summary. Alternatively spliced transcript variants have been found for this gene. The smaller protein isoform encoded by the shorter transcript variant is found only in HIV-1 infected cells. [provided by RefSeq, Jul 2010]
- Expression. Ubiquitous expression in testis (RPKM 19.7), bone marrow (RPKM 11.0) and 25 other tissues See more
- Preferred Names OTU domain-containing protein 4
- Names: HIV-1 induced protein HIN-1
-
HIV-1 promotor insertion revealed by selective detection of chimeric provirus-host gene transcripts. Raineri I, et al. Nucleic Acids Res, 1992 Dec 11. PMID 1475186, Free PMC Article https://www.ncbi.nlm.nih.gov/pubmed/1475186/This shows for the first time that HIV-1 can activate transcription of host cellular genes by promotor insertion in a fashion similar to slow-transforming avian and murine retroviruses.
-
OTUD4 Is a Phospho-Activated K63 Deubiquitinase that Regulates MyD88-Dependent Signaling. Zhao Y, et al. Mol Cell, 2018 Feb 1. PMID 29395066 Ubiquitination is a major mechanism that regulates numerous cellular processes, including autophagy, DNA damage signaling, and inflammation. While hundreds of ubiquitin ligases exist to conjugate ubiquitin onto substrates, approximately 100 deubiquitinases (DUBs) are encoded by the human genome. Thus, deubiquitinases are likely regulated by unidentified mechanisms to target distinct substrates and cellular functions. Here, we demonstrate that the deubiquitinase OTUD4, which nominally encodes a K48-specific deubiquitinase, is phosphorylated near its catalytic domain, activating a latent K63-specific deubiquitinase. Besides phosphorylation, this latter activity requires an adjacent ubiquitin-interacting motif, which increases the affinity of OTUD4 for K63-linked chains. We reveal the Toll-like receptor (TLR)-associated factor MyD88 as a target of this K63 deubiquitinase activity. Consequently, TLR-mediated activation of NF-κB is negatively regulated by OTUD4, and macrophages from Otud4-/- mice exhibit increased inflammatory signaling upon TLR stimulation. Our results reveal insights into how a deubiquitinase may modulate diverse processes through post-translational modification.
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Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. Margolin DH, et al. N Engl J Med, 2013 May 23. PMID 23656588, Free PMC Article(Suom. Seuraa vaikea harvinainen oireyhtymä, jos taustalla on sellainen kombinoitu mutaatio, jossa RBR-tyyppinen RNF proteiini RNF216, E3 ubikitiiniligaasi, ja OTUD4,deubikitinaasi, ovat molemmat mutatoituneita geenejä )
See citations in PubMed for homologs of this gene provided by HomoloGene
GeneRIFWhat's
a GeneRIF?s: Gene References Into Functions
-
OTUD4 is a positive regulator of ALKBH2 and ALKBH3, two DNA demethylases critical for alkylation repair. Repair of DNA alkylation damage is critical for genomic stability and involves multiple conserved enzymatic pathways. Alkylation damage resistance, which is critical in cancer chemotherapy, depends on the overexpression of alkylation repair proteins. However, the mechanisms responsible for this upregulation are unknown. Here, we show that an OTU domain deubiquitinase, OTUD4, is a positive regulator of ALKBH2 and ALKBH3, two DNA demethylases critical for alkylation repair. Remarkably, we find that OTUD4 catalytic activity is completely dispensable for this function. Rather, OTUD4 is a scaffold for USP7 and USP9X, two deubiquitinases that act directly on the AlkB proteins. Moreover, we show that loss of OTUD4, USP7, or USP9X in tumor cells makes them significantly more sensitive to alkylating agents. Taken together, this work reveals a novel, noncanonical mechanism by which an OTU family deubiquitinase regulates its substrates, and provides multiple new targets for alkylation chemotherapy sensitization of tumors.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475402/
Peptide history
and structure:
OTU domain-containing protein 4 isoform 3 [Homo
sapiens]
NCBI Reference Sequence: NP_001096123.1Identical Proteins FASTA Graphics
LOCUS NP_001096123 1049 aa linear PRI 24-JUN-2018 DEFINITION OTU domain-containing protein 4 isoform 3 [Homo sapiens]. ACCESSION NP_001096123 VERSION NP_001096123.1 DBSOURCE REFSEQ: accession NM_001102653.1 KEYWORDS RefSeq. SOURCE Homo sapiens (human) ORGANISM Homo sapiens Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo. REFERENCE 1 (residues 1 to 1049) AUTHORS Zhao Y, Mudge MC, Soll JM, Rodrigues RB, Byrum AK, Schwarzkopf EA, Bradstreet TR, Gygi SP, Edelson BT and Mosammaparast N. TITLE OTUD4 Is a Phospho-Activated K63 Deubiquitinase that Regulates MyD88-Dependent Signaling JOURNAL Mol. Cell 69 (3), 505-516 (2018) PUBMED 29395066 REFERENCE 2 (residues 1 to 1049) AUTHORS Louis M, Hofmann K and Broemer M. TITLE Evolutionary Loss of Activity in De-Ubiquitylating Enzymes of the OTU Family JOURNAL PLoS ONE 10 (11), e0143227 (2015) PUBMED 26588485 REMARK GeneRIF: There is an evolutionary loss of activity in de-ubiquitylating enzymes of the OTU family, OTUD4, otu, and CG3251. Publication Status: Online-Only REFERENCE 3 (residues 1 to 1049) AUTHORS Zhao Y, Majid MC, Soll JM, Brickner JR, Dango S and Mosammaparast N. TITLE Noncanonical regulation of alkylation damage resistance by the OTUD4 deubiquitinase JOURNAL EMBO J. 34 (12), 1687-1703 (2015) PUBMED 25944111 REMARK GeneRIF: OTUD4 is a positive regulator of ALKBH2 and ALKBH3, two DNA demethylases critical for alkylation repair. REFERENCE 4 (residues 1 to 1049) AUTHORS Mevissen TE, Hospenthal MK, Geurink PP, Elliott PR, Akutsu M, Arnaudo N, Ekkebus R, Kulathu Y, Wauer T, El Oualid F, Freund SM, Ovaa H and Komander D. TITLE OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis JOURNAL Cell 154 (1), 169-184 (2013) PUBMED 23827681 REFERENCE 5 (residues 1 to 1049) AUTHORS Margolin DH, Kousi M, Chan YM, Lim ET, Schmahmann JD, Hadjivassiliou M, Hall JE, Adam I, Dwyer A, Plummer L, Aldrin SV, O'Rourke J, Kirby A, Lage K, Milunsky A, Milunsky JM, Chan J, Hedley-Whyte ET, Daly MJ, Katsanis N and Seminara SB. TITLE Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination JOURNAL N. Engl. J. Med. 368 (21), 1992-2003 (2013) PUBMED 23656588 REMARK GeneRIF: The syndrome of hypogonadotropic hypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by the combination of mutations in RNF216 and OTUD4 REFERENCE 6 (residues 1 to 1049) AUTHORS Beausoleil SA, Villen J, Gerber SA, Rush J and Gygi SP. TITLE A probability-based approach for high-throughput protein phosphorylation analysis and site localization JOURNAL Nat. Biotechnol. 24 (10), 1285-1292 (2006) PUBMED 16964243 REFERENCE 7 (residues 1 to 1049) AUTHORS Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD and Comb MJ. TITLE Immunoaffinity profiling of tyrosine phosphorylation in cancer cells JOURNAL Nat. Biotechnol. 23 (1), 94-101 (2005) PUBMED 15592455 REFERENCE 8 (residues 1 to 1049) AUTHORS Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villen J, Li J, Cohn MA, Cantley LC and Gygi SP. TITLE Large-scale characterization of HeLa cell nuclear phosphoproteins JOURNAL Proc. Natl. Acad. Sci. U.S.A. 101 (33), 12130-12135 (2004) PUBMED 15302935 REFERENCE 9 (residues 1 to 1049) AUTHORS Brill LM, Salomon AR, Ficarro SB, Mukherji M, Stettler-Gill M and Peters EC. TITLE Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry JOURNAL Anal. Chem. 76 (10), 2763-2772 (2004) PUBMED 15144186 REFERENCE 10 (residues 1 to 1049) AUTHORS Raineri I and Senn HP. TITLE HIV-1 promotor insertion revealed by selective detection of chimeric provirus-host gene transcripts JOURNAL Nucleic Acids Res. 20 (23), 6261-6266 (1992) PUBMED 1475186 COMMENT REVIEWED REFSEQ: This record has been curated by NCBI staff. The reference sequence was derived from DB446926.2, BC118572.1 and AC096757.3. This sequence is a reference standard in the RefSeqGene project. Summary: Alternatively spliced transcript variants have been found for this gene. The smaller protein isoform encoded by the shorter transcript variant is found only in HIV-1 infected cells. [provided by RefSeq, Jul 2010]. Transcript Variant: This variant (3) represents the longer transcript and encodes the longer isoform (3). Sequence Note: This RefSeq record was created from transcript and genomic sequence data because no single transcript was available for the full length of the gene. The extent of this transcript is supported by transcript alignments. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. ##Evidence-Data-START## Transcript exon combination :: AK302581.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support SAMEA1965299, SAMEA1966682 [ECO:0000350] ##Evidence-Data-END## FEATURES Location/Qualifiers source 1..1049 /organism="Homo sapiens" /db_xref="taxon:9606" /chromosome="4" /map="4q31.21" Protein 1..1049 /product="OTU domain-containing protein 4 isoform 3" /EC_number="3.4.19.12" /note="OTU domain-containing protein 4; HIV-1 induced protein HIN-1" /calculated_mol_wt=116951 Region <3 ..="">56 /region_name="OTU" /note="OTU-like cysteine protease; cl19932" /db_xref="CDD:303090" CDS 1..1049 /gene="OTUD4" /gene_synonym="DUBA6; HIN1; HSHIN1" /coded_by="NM_001102653.1:139..3288" /note="isoform 3 is encoded by transcript variant 3" /db_xref="CCDS:CCDS47139.1" /db_xref="GeneID:54726" /db_xref="HGNC:HGNC:24949" /db_xref="MIM:611744" ORIGIN 1 macihylren rekfeafieg sfeeylkrle npqewvgqve isalslmyrk dfiiyrepnv 61 spsqvtennf pekvllcfsn gnhydivypi kykessamcq sllyellyek vfktdvskiv 121 meldtlevad ednseisdse ddscksktaa aaadvngfkp lsgneqlknn gnstslplsr 181 kvlkslnpav yrnveyeiwl kskqaqqkrd ysiaaglqye vgdkcqvrld hngkflnadv 241 qgihsengpv lveelgkkht sknlkapppe swntvsgkkm kkpstsgqnf hsdvdyrgpk 301 npskpikaps alpprlqhps gvrqhafssh ssgsqsqkfs sehknlsrtp sqiirkpdre 361 rvedfdhtsr esnyfglspe errekqaiee srllyeiqnr deqafpalss ssvnqsasqs 421 snpcvqrkss hvgdrkgsrr rmdteerkdk dsihghsqld krpepstlen itddkyatvs 481 spskskklec pspaeqkpae hvslsnpapl lvspevhltp avpslpatvp awpsepttfg 541 ptgvpapipv lsvtqtlttg pdsavsqahl tpspvpvsiq avnqplmplp qtlslyqdpl 601 ypgfpcnekg draivppysl cqtgedlpkd knilrfffnl gvkayscpmw aphsylyplh 661 qaylaacrmy pkvpvpvyph npwfqeapaa qnesdctctd ahfpmqteas vngqmpqpei 721 gpptfssplv ippsqvsesh gqlsyqadle setpgqllha dyeeslsgkn mfpqpsfgpn 781 pflgpvpiap pffphvwygy pfqgfienpv mrqnivlpsd ekgeldlsle nldlskdcgs 841 vstvdefpea rgehvhslpe asvsskpdeg rteqssqtrk adtalasipp vaegkahppt 901 qilnreretv pvelepkrti qslkektekv kdpktaadvv spgansvdsr vqrpkeesse 961 denevsnilr sgrskqfynq tygsrkyksd wgysgrggyq hvrseeswkg qpsrsrdegy 1021 qyhrnvrgrp frgdrrrsgm gdghrgqht //
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