OTUL_MOUSE
ID OTUL_MOUSE Reviewed; 352 AA.
AC Q3UCV8; Q3UY59; Q5M8N1; Q8R027;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT 11-OCT-2005, sequence version 1.
DT 03-AUG-2022, entry version 109.
DE RecName: Full=Ubiquitin thioesterase otulin {ECO:0000305};
DE EC=3.4.19.12 {ECO:0000269|PubMed:23708998, ECO:0000269|PubMed:29950720};
DE AltName: Full=Deubiquitinating enzyme otulin {ECO:0000250|UniProtKB:Q96BN8};
DE AltName: Full=OTU domain-containing deubiquitinase with linear linkage specificity {ECO:0000250|UniProtKB:Q96BN8};
DE AltName: Full=Ubiquitin thioesterase Gumby {ECO:0000303|PubMed:23708998};
GN Name=Otulin {ECO:0000312|MGI:MGI:3577015};
GN Synonyms=Fam105b {ECO:0000312|MGI:MGI:3577015},
GN Gum {ECO:0000303|PubMed:23708998};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Bone marrow, and Olfactory bulb;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 106-352.
RC TISSUE=Mammary gland, and Molar;
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 [4]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE,
RP DEVELOPMENTAL STAGE, ACTIVE SITE, INTERACTION WITH RNF31 AND DVL2, AND
RP MUTAGENESIS OF TRP-96; CYS-129; ASP-336 AND 349-GLU--VAL-352.
RX PubMed=23708998; DOI=10.1038/nature12296;
RA Rivkin E., Almeida S.M., Ceccarelli D.F., Juang Y.C., Maclean T.A.,
RA Srikumar T., Huang H., Dunham W.H., Fukumura R., Xie G., Gondo Y.,
RA Raught B., Gingras A.C., Sicheri F., Cordes S.P.;
RT "The linear ubiquitin-specific deubiquitinase gumby regulates
RT angiogenesis.";
RL Nature 498:318-324(2013).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=27523608; DOI=10.1016/j.cell.2016.07.019;
RA Damgaard R.B., Walker J.A., Marco-Casanova P., Morgan N.V.,
RA Titheradge H.L., Elliott P.R., McHale D., Maher E.R., McKenzie A.N.,
RA Komander D.;
RT "The deubiquitinase OTULIN is an essential negative regulator of
RT inflammation and autoimmunity.";
RL Cell 166:1215-1230(2016).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF CYS-129.
RX PubMed=29950720; DOI=10.1038/s41586-018-0256-2;
RA Heger K., Wickliffe K.E., Ndoja A., Zhang J., Murthy A., Dugger D.L.,
RA Maltzman A., de Sousa E Melo F., Hung J., Zeng Y., Verschueren E.,
RA Kirkpatrick D.S., Vucic D., Lee W.P., Roose-Girma M., Newman R.J.,
RA Warming S., Hsiao Y.C., Komuves L.G., Webster J.D., Newton K., Dixit V.M.;
RT "OTULIN limits cell death and inflammation by deubiquitinating LUBAC.";
RL Nature 559:120-124(2018).
CC -!- FUNCTION: Deubiquitinase that specifically removes linear ('Met-1'-
CC linked) polyubiquitin chains to substrates and acts as a regulator of
CC angiogenesis and innate immune response (PubMed:23708998,
CC PubMed:27523608, PubMed:29950720). Required during angiogenesis,
CC craniofacial and neuronal development by regulating the canonical Wnt
CC signaling together with the LUBAC complex (PubMed:23708998). Acts as a
CC negative regulator of NF-kappa-B by regulating the activity of the
CC LUBAC complex (By similarity). OTULIN function is mainly restricted to
CC homeostasis of the LUBAC complex: acts by removing 'Met-1'-linked
CC autoubiquitination of the LUBAC complex, thereby preventing
CC inactivation of the LUBAC complex (PubMed:29950720). Acts as a key
CC negative regulator of inflammation by restricting spontaneous
CC inflammation and maintaining immune homeostasis (PubMed:27523608,
CC PubMed:29950720). In myeloid cell, required to prevent unwarranted
CC secretion of cytokines leading to inflammation and autoimmunity by
CC restricting linear polyubiquitin formation (PubMed:27523608). Plays a
CC role in innate immune response by restricting linear polyubiquitin
CC formation on LUBAC complex in response to NOD2 stimulation, probably to
CC limit NOD2-dependent pro-inflammatory signaling (By similarity).
CC {ECO:0000250|UniProtKB:Q96BN8, ECO:0000269|PubMed:23708998,
CC ECO:0000269|PubMed:27523608, ECO:0000269|PubMed:29950720}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide
CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-
CC residue protein attached to proteins as an intracellular targeting
CC signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:23708998,
CC ECO:0000269|PubMed:29950720};
CC -!- SUBUNIT: Interacts (via the PUB domain) with RNF31 (via the PIM motif);
CC the interaction is direct (PubMed:23708998). Interacts with DVL2
CC (PubMed:23708998). {ECO:0000269|PubMed:23708998}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:23708998}.
CC -!- DEVELOPMENTAL STAGE: Enriched in a subset of endothelial cells near
CC presumptive tips of vessels and vascular buds (at protein level).
CC {ECO:0000269|PubMed:23708998}.
CC -!- DOMAIN: The specificity for linear polyubiquitin is given by the 'Glu-
CC 16' residue in ubiquitin chain. {ECO:0000250|UniProtKB:Q96BN8}.
CC -!- DOMAIN: The PIM (PUB-interaction motif) motif mediates interaction with
CC the PUB domain of RNF31. Does not interact with other PUB domain-
CC containing proteins. Phosphorylation at Tyr-56 prevents interaction
CC with RNF31. {ECO:0000250|UniProtKB:Q96BN8}.
CC -!- PTM: Ubiquitinated. {ECO:0000250|UniProtKB:Q96BN8}.
CC -!- PTM: Acetylated. {ECO:0000250|UniProtKB:Q96BN8}.
CC -!- PTM: Phosphorylated. Phosphorylation at Tyr-56 prevents interaction
CC with RNF31; dephosphorylation promotes interaction with RNF31 and the
CC LUBAC complex. {ECO:0000250|UniProtKB:Q96BN8}.
CC -!- DISRUPTION PHENOTYPE: Embryonic lethality (PubMed:23708998,
CC PubMed:27523608). Specific deletion in immune cells leads to acute
CC systemic inflammation characterized by rapid weight loss, increased
CC levels of pro-inflammatory cytokines in serum, neutrophilia with all
CC the hallmarks of emergency granulopoiesis (PubMed:27523608). Specific
CC deletion in T- or B-cells generates healthy mice with no overt
CC inflammatory phenotypes (PubMed:27523608). In contrast, specific
CC deletion in myeloid cells results in a strong inflammatory phenotype,
CC characterized by chronic inflammation and autoimmunity, caused by
CC sterile autoactivation of inflammatory pathways (PubMed:27523608).
CC {ECO:0000269|PubMed:23708998, ECO:0000269|PubMed:27523608}.
CC -!- SIMILARITY: Belongs to the peptidase C65 family. Otulin subfamily.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH87945.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAE22354.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AK134955; BAE22354.1; ALT_INIT; mRNA.
DR EMBL; AK150371; BAE29504.1; -; mRNA.
DR EMBL; GL456173; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC028541; AAH28541.1; -; mRNA.
DR EMBL; BC087945; AAH87945.1; ALT_INIT; mRNA.
DR CCDS; CCDS49586.1; -.
DR RefSeq; NP_001013814.2; NM_001013792.2.
DR AlphaFoldDB; Q3UCV8; -.
DR SMR; Q3UCV8; -.
DR BioGRID; 240910; 3.
DR STRING; 10090.ENSMUSP00000057893; -.
DR iPTMnet; Q3UCV8; -.
DR PhosphoSitePlus; Q3UCV8; -.
DR EPD; Q3UCV8; -.
DR MaxQB; Q3UCV8; -.
DR PaxDb; Q3UCV8; -.
DR PeptideAtlas; Q3UCV8; -.
DR PRIDE; Q3UCV8; -.
DR ProteomicsDB; 294136; -.
DR Antibodypedia; 56178; 94 antibodies from 21 providers.
DR DNASU; 432940; -.
DR Ensembl; ENSMUST00000059662; ENSMUSP00000057893; ENSMUSG00000046034.
DR GeneID; 432940; -.
DR KEGG; mmu:432940; -.
DR UCSC; uc007vjr.1; mouse.
DR CTD; 90268; -.
DR MGI; MGI:3577015; Otulin.
DR VEuPathDB; HostDB:ENSMUSG00000046034; -.
DR eggNOG; ENOG502QTB8; Eukaryota.
DR GeneTree; ENSGT00390000009802; -.
DR HOGENOM; CLU_051856_1_1_1; -.
DR InParanoid; Q3UCV8; -.
DR OMA; TDPPRDW; -.
DR OrthoDB; 1416236at2759; -.
DR PhylomeDB; Q3UCV8; -.
DR TreeFam; TF328709; -.
DR Reactome; R-MMU-5357905; Regulation of TNFR1 signaling.
DR Reactome; R-MMU-8866652; Synthesis of active ubiquitin: roles of E1 and E2 enzymes.
DR BioGRID-ORCS; 432940; 9 hits in 76 CRISPR screens.
DR ChiTaRS; Otulin; mouse.
DR PRO; PR:Q3UCV8; -.
DR Proteomes; UP000000589; Chromosome 15.
DR RNAct; Q3UCV8; protein.
DR Bgee; ENSMUSG00000046034; Expressed in yolk sac and 218 other tissues.
DR ExpressionAtlas; Q3UCV8; baseline and differential.
DR Genevisible; Q3UCV8; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0008234; F:cysteine-type peptidase activity; IMP:UniProtKB.
DR GO; GO:0045087; P:innate immune response; ISS:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IMP:UniProtKB.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IMP:UniProtKB.
DR GO; GO:0070431; P:nucleotide-binding oligomerization domain containing 2 signaling pathway; ISS:UniProtKB.
DR GO; GO:1990108; P:protein linear deubiquitination; IDA:UniProtKB.
DR GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; IDA:UniProtKB.
DR GO; GO:0010803; P:regulation of tumor necrosis factor-mediated signaling pathway; IMP:UniProtKB.
DR GO; GO:0002040; P:sprouting angiogenesis; IMP:UniProtKB.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR Gene3D; 1.20.1300.20; -; 1.
DR Gene3D; 3.30.200.60; -; 1.
DR InterPro; IPR023235; FAM105.
DR InterPro; IPR023237; Otulin.
DR InterPro; IPR042468; Peptidase_C65_otubain_sub1.
DR InterPro; IPR042467; Peptidase_C65_otubain_sub2.
DR PANTHER; PTHR33662; PTHR33662; 1.
DR Pfam; PF16218; Peptidase_C101; 1.
DR PRINTS; PR02055; PROTEINF105.
DR PRINTS; PR02057; PROTEINF105B.
PE 1: Evidence at protein level;
KW Acetylation; Angiogenesis; Coiled coil; Cytoplasm; Hydrolase; Immunity;
KW Innate immunity; Phosphoprotein; Protease; Reference proteome;
KW Thiol protease; Ubl conjugation; Ubl conjugation pathway;
KW Wnt signaling pathway.
FT CHAIN 1..352
FT /note="Ubiquitin thioesterase otulin"
FT /id="PRO_0000261638"
FT DOMAIN 118..346
FT /note="OTU"
FT REGION 1..49
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 95..96
FT /note="Linear diubiquitin binding"
FT /evidence="ECO:0000250|UniProtKB:Q96BN8"
FT REGION 124..126
FT /note="Linear diubiquitin binding"
FT /evidence="ECO:0000250|UniProtKB:Q96BN8"
FT REGION 255..259
FT /note="Linear diubiquitin binding"
FT /evidence="ECO:0000250|UniProtKB:Q96BN8"
FT REGION 283..289
FT /note="Linear diubiquitin binding"
FT /evidence="ECO:0000250|UniProtKB:Q96BN8"
FT REGION 336..338
FT /note="Linear diubiquitin binding"
FT /evidence="ECO:0000250|UniProtKB:Q96BN8"
FT COILED 49..73
FT /evidence="ECO:0000255"
FT MOTIF 52..57
FT /note="PIM motif"
FT /evidence="ECO:0000250|UniProtKB:Q96BN8"
FT MOTIF 349..352
FT /note="PDZ-binding"
FT ACT_SITE 126
FT /evidence="ECO:0000269|PubMed:23708998"
FT ACT_SITE 129
FT /note="Nucleophile"
FT /evidence="ECO:0000269|PubMed:23708998"
FT ACT_SITE 339
FT /evidence="ECO:0000269|PubMed:23708998"
FT SITE 314
FT /note="Linear diubiquitin binding"
FT /evidence="ECO:0000250|UniProtKB:Q96BN8"
FT MOD_RES 56
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q96BN8"
FT MUTAGEN 96
FT /note="W->R: In Gum(W96R) mutant; defects in embryonic
FT angiogenesis. Embryos appear normal before 11.5 dpc but die
FT between 12.5 dpc-14 dpc, probably due to defects in
FT organization of branching vascular networks in the head and
FT trunk."
FT /evidence="ECO:0000269|PubMed:23708998"
FT MUTAGEN 129
FT /note="C->A,S: Abolishes deubiquitinase activity without
FT affecting interaction with RNF31. Lethality at midgestation
FT in knockin mice caused by inactivation of the LUBAC
FT complex, leading to cell death mediated by TNFR1 and
FT RIPK1."
FT /evidence="ECO:0000269|PubMed:23708998,
FT ECO:0000269|PubMed:29950720"
FT MUTAGEN 336
FT /note="D->E: In Gum(D366E) mutant; defects in embryonic
FT angiogenesis. Weaker mutant compared to Gum(W96R) mutant."
FT /evidence="ECO:0000269|PubMed:23708998"
FT MUTAGEN 349..352
FT /note="ETSV->AAAA: Does not affect interaction with RNF31."
FT /evidence="ECO:0000269|PubMed:23708998"
SQ SEQUENCE 352 AA; 40320 MW; 435B9B3F4BDEEDDA CRC64;
MSRGTMPQPG AWPGASCAET PAREAGAAAR DGGKVTAGAQ PRAATRCPAE HEEDMYRAAD
EIEKEKELLI HERGISEPRL SVAPEMDIMD YCKKEWRGNT QKATCMKKGY EEVSQKFTSI
RRVRGDNYCA LRATLFQAMS QLAELPPWLQ DLELILLPEK LINKYTWIKQ WKLGLKFDGK
SEDLVEKIKE SLALLRKKWV SLAAMKTAEA RQTACDELFT NEEEEYSLYE AVKFLMLNRA
IELYDDKEKG KEVPFFSVLL FARDTSNDPE QLLRNHLNQV GHTGGLEQVE MFLLAYAVRH
SIRVYRLSKY NTEEFITVYP TDPPKDWPMV TLIAEDDRHY NIPVRVCEET SV
