OTUL_HUMAN
ID OTUL_HUMAN Reviewed; 352 AA.
AC Q96BN8; D3DTD3; Q8NAS0; Q96IA3;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT 28-NOV-2006, sequence version 3.
DT 03-AUG-2022, entry version 136.
DE RecName: Full=Ubiquitin thioesterase otulin {ECO:0000305};
DE EC=3.4.19.12 {ECO:0000269|PubMed:23746843, ECO:0000269|PubMed:23827681, ECO:0000269|PubMed:27523608, ECO:0000269|PubMed:28919039};
DE AltName: Full=Deubiquitinating enzyme otulin {ECO:0000303|PubMed:23806334};
DE AltName: Full=OTU domain-containing deubiquitinase with linear linkage specificity {ECO:0000303|PubMed:23806334};
DE AltName: Full=Ubiquitin thioesterase Gumby {ECO:0000250|UniProtKB:Q3UCV8};
GN Name=OTULIN {ECO:0000303|PubMed:23806334, ECO:0000312|HGNC:HGNC:25118};
GN Synonyms=FAM105B {ECO:0000312|HGNC:HGNC:25118};
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 [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Ovary, and Prostate;
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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 123-298.
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 [5]
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 [6]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=23827681; DOI=10.1016/j.cell.2013.05.046;
RA Mevissen T.E., Hospenthal M.K., Geurink P.P., Elliott P.R., Akutsu M.,
RA Arnaudo N., Ekkebus R., Kulathu Y., Wauer T., El Oualid F., Freund S.M.,
RA Ovaa H., Komander D.;
RT "OTU deubiquitinases reveal mechanisms of linkage specificity and enable
RT ubiquitin chain restriction analysis.";
RL Cell 154:169-184(2013).
RN [7]
RP FUNCTION, AND MUTAGENESIS OF TRP-96 AND CYS-129.
RX PubMed=23806334; DOI=10.1016/j.molcel.2013.06.004;
RA Fiil B.K., Damgaard R.B., Wagner S.A., Keusekotten K., Fritsch M.,
RA Bekker-Jensen S., Mailand N., Choudhary C., Komander D., Gyrd-Hansen M.;
RT "OTULIN restricts Met1-linked ubiquitination to control innate immune
RT signaling.";
RL Mol. Cell 50:818-830(2013).
RN [8]
RP FUNCTION.
RX PubMed=26670046; DOI=10.1016/j.celrep.2015.11.009;
RA Draber P., Kupka S., Reichert M., Draberova H., Lafont E., de Miguel D.,
RA Spilgies L., Surinova S., Taraborrelli L., Hartwig T., Rieser E.,
RA Martino L., Rittinger K., Walczak H.;
RT "LUBAC-recruited CYLD and A20 regulate gene activation and cell death by
RT exerting opposing effects on linear ubiquitin in signaling complexes.";
RL Cell Rep. 13:2258-2272(2015).
RN [9]
RP FUNCTION.
RX PubMed=26997266; DOI=10.1016/j.celrep.2016.02.062;
RA Hrdinka M., Fiil B.K., Zucca M., Leske D., Bagola K., Yabal M.,
RA Elliott P.R., Damgaard R.B., Komander D., Jost P.J., Gyrd-Hansen M.;
RT "CYLD limits Lys63- and Met1-linked ubiquitin at receptor complexes to
RT regulate innate immune signaling.";
RL Cell Rep. 14:2846-2858(2016).
RN [10]
RP INVOLVEMENT IN AIPDS, FUNCTION, INTERACTION WITH RNF31, VARIANT AIPDS
RP PRO-272, AND CHARACTERIZATION OF VARIANT AIPDS PRO-272.
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 [11]
RP INTERACTION WITH RNF31, DOMAIN, AND MUTAGENESIS OF TYR-56.
RX PubMed=27458237; DOI=10.15252/embr.201642592;
RA Schlicher L., Wissler M., Preiss F., Brauns-Schubert P., Jakob C.,
RA Dumit V., Borner C., Dengjel J., Maurer U.;
RT "SPATA2 promotes CYLD activity and regulates TNF-induced NF-kappaB
RT signaling and cell death.";
RL EMBO Rep. 17:1485-1497(2016).
RN [12]
RP INVOLVEMENT IN AIPDS, FUNCTION, VARIANTS AIPDS CYS-244 AND PRO-272, AND
RP CHARACTERIZATION OF VARIANTS AIPDS CYS-244 AND PRO-272.
RX PubMed=27559085; DOI=10.1073/pnas.1612594113;
RA Zhou Q., Yu X., Demirkaya E., Deuitch N., Stone D., Tsai W.L., Kuehn H.S.,
RA Wang H., Yang D., Park Y.H., Ombrello A.K., Blake M., Romeo T.,
RA Remmers E.F., Chae J.J., Mullikin J.C., Guezel F., Milner J.D., Boehm M.,
RA Rosenzweig S.D., Gadina M., Welch S.B., Oezen S., Topaloglu R., Abinun M.,
RA Kastner D.L., Aksentijevich I.;
RT "Biallelic hypomorphic mutations in a linear deubiquitinase define
RT otulipenia, an early-onset autoinflammatory disease.";
RL Proc. Natl. Acad. Sci. U.S.A. 113:10127-10132(2016).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.3 ANGSTROMS) OF MUTANT ASP-336, X-RAY
RP CRYSTALLOGRAPHY (1.35 ANGSTROMS) IN COMPLEX WITH LINEAR DIUBIQUITIN,
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR
RP LOCATION, PHOSPHORYLATION, UBIQUITINATION, ACETYLATION, MUTAGENESIS OF
RP TYR-91; TRP-96; 100-THR--LYS-102; CYS-129; LEU-259; GLU-314; ASP-336;
RP HIS-339 AND ASN-341, AND ACTIVE SITE.
RX PubMed=23746843; DOI=10.1016/j.cell.2013.05.014;
RA Keusekotten K., Elliott P.R., Glockner L., Fiil B.K., Damgaard R.B.,
RA Kulathu Y., Wauer T., Hospenthal M.K., Gyrd-Hansen M., Krappmann D.,
RA Hofmann K., Komander D.;
RT "OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked
RT polyubiquitin.";
RL Cell 153:1312-1326(2013).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 79-352 OF MUTANT CYS-129, X-RAY
RP CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 79-352 OF MUTANT CYS-129 IN COMPLEX WITH
RP LINEAR DIUBIQUITIN, FUNCTION, INTERACTION WITH RNF31 AND DVL2, MUTAGENESIS
RP OF CYS-129, AND ACTIVE SITE.
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 [15]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 49-67 IN COMPLEX WITH RNF31,
RP FUNCTION, INTERACTION WITH RNF31, DOMAIN, PHOSPHORYLATION AT TYR-56, AND
RP MUTAGENESIS OF ASP-54; MET-55 AND TYR-56.
RX PubMed=24726323; DOI=10.1016/j.molcel.2014.03.018;
RA Elliott P.R., Nielsen S.V., Marco-Casanova P., Fiil B.K., Keusekotten K.,
RA Mailand N., Freund S.M., Gyrd-Hansen M., Komander D.;
RT "Molecular basis and regulation of OTULIN-LUBAC interaction.";
RL Mol. Cell 54:335-348(2014).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 52-61 IN COMPLEX WITH RNF31,
RP FUNCTION, INTERACTION WITH RNF31, DOMAIN, PHOSPHORYLATION AT TYR-56, ACTIVE
RP SITE, AND MUTAGENESIS OF TYR-56 AND CYS-129.
RX PubMed=24726327; DOI=10.1016/j.molcel.2014.03.016;
RA Schaeffer V., Akutsu M., Olma M.H., Gomes L.C., Kawasaki M., Dikic I.;
RT "Binding of OTULIN to the PUB domain of HOIP controls NF-kappaB
RT signaling.";
RL Mol. Cell 54:349-361(2014).
RN [17] {ECO:0007744|PDB:5OE7}
RP X-RAY CRYSTALLOGRAPHY (2.95 ANGSTROMS) OF 80-350, FUNCTION, CATALYTIC
RP ACTIVITY, AND MUTAGENESIS OF CYS-129.
RX PubMed=28919039; DOI=10.1016/j.chembiol.2017.08.006;
RA Weber A., Elliott P.R., Pinto-Fernandez A., Bonham S., Kessler B.M.,
RA Komander D., El Oualid F., Krappmann D.;
RT "A linear diubiquitin-based probe for efficient and selective detection of
RT the deubiquitinating enzyme OTULIN.";
RL Cell Chem. Biol. 24:1299-1313(2017).
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:26997266,
CC PubMed:23708998, PubMed:23746843, PubMed:23806334, PubMed:23827681,
CC PubMed:27523608, PubMed:27559085, PubMed:24726323, PubMed:24726327,
CC PubMed:28919039). Required during angiogenesis, craniofacial and
CC neuronal development by regulating the canonical Wnt signaling together
CC with the LUBAC complex (PubMed:23708998). Acts as a negative regulator
CC of NF-kappa-B by regulating the activity of the LUBAC complex
CC (PubMed:23746843, PubMed:23806334). OTULIN function is mainly
CC restricted to homeostasis of the LUBAC complex: acts by removing 'Met-
CC 1'-linked autoubiquitination of the LUBAC complex, thereby preventing
CC inactivation of the LUBAC complex (PubMed:26670046). Acts as a key
CC negative regulator of inflammation by restricting spontaneous
CC inflammation and maintaining immune homeostasis (PubMed:27523608). In
CC myeloid cell, required to prevent unwarranted secretion of cytokines
CC leading to inflammation and autoimmunity by restricting linear
CC polyubiquitin formation (PubMed:27523608). Plays a role in innate
CC immune response by restricting linear polyubiquitin formation on LUBAC
CC complex in response to NOD2 stimulation, probably to limit NOD2-
CC dependent pro-inflammatory signaling (PubMed:23806334).
CC {ECO:0000269|PubMed:23708998, ECO:0000269|PubMed:23746843,
CC ECO:0000269|PubMed:23806334, ECO:0000269|PubMed:23827681,
CC ECO:0000269|PubMed:24726323, ECO:0000269|PubMed:24726327,
CC ECO:0000269|PubMed:26670046, ECO:0000269|PubMed:26997266,
CC ECO:0000269|PubMed:27523608, ECO:0000269|PubMed:27559085,
CC ECO:0000269|PubMed:28919039}.
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:23746843,
CC ECO:0000269|PubMed:23827681, ECO:0000269|PubMed:27523608,
CC ECO:0000269|PubMed:28919039};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=7.98 uM for linear diubiquitin {ECO:0000269|PubMed:23746843};
CC Note=kcat is 6.3 sec(-1) with linear diubiquitin as substrate.
CC {ECO:0000269|PubMed:23746843};
CC -!- SUBUNIT: Interacts (via the PUB domain) with RNF31 (via the PIM motif);
CC the interaction is direct (PubMed:23708998, PubMed:23746843,
CC PubMed:24726323, PubMed:24726327, PubMed:27523608). Interacts with DVL2
CC (By similarity). {ECO:0000250|UniProtKB:Q3UCV8,
CC ECO:0000269|PubMed:23708998, ECO:0000269|PubMed:23746843,
CC ECO:0000269|PubMed:24726323, ECO:0000269|PubMed:24726327,
CC ECO:0000269|PubMed:27523608}.
CC -!- INTERACTION:
CC Q96BN8; Q15038: DAZAP2; NbExp=6; IntAct=EBI-750730, EBI-724310;
CC Q96BN8; Q92567: FAM168A; NbExp=3; IntAct=EBI-750730, EBI-7957930;
CC Q96BN8; Q92567-2: FAM168A; NbExp=3; IntAct=EBI-750730, EBI-11978259;
CC Q96BN8; Q6GQQ9: OTUD7B; NbExp=3; IntAct=EBI-750730, EBI-527784;
CC Q96BN8; Q8WV19: SFT2D1; NbExp=3; IntAct=EBI-750730, EBI-2854842;
CC Q96BN8; Q8N0X7: SPART; NbExp=3; IntAct=EBI-750730, EBI-2643803;
CC Q96BN8; Q92537: SUSD6; NbExp=3; IntAct=EBI-750730, EBI-2866213;
CC Q96BN8; Q8WW34-2: TMEM239; NbExp=3; IntAct=EBI-750730, EBI-11528917;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:23746843}.
CC -!- DOMAIN: The specificity for linear polyubiquitin is given by the 'Glu-
CC 16' residue in ubiquitin chain. {ECO:0000269|PubMed:23746843}.
CC -!- DOMAIN: The PIM (PUB-interaction motif) motif mediates interaction with
CC the PUB domain of RNF31 (PubMed:24726323, PubMed:24726327,
CC PubMed:27458237). Does not interact with other PUB domain-containing
CC proteins. Phosphorylation at Tyr-56 prevents interaction with RNF31
CC (PubMed:24726323, PubMed:24726327). {ECO:0000269|PubMed:24726323,
CC ECO:0000269|PubMed:24726327, ECO:0000269|PubMed:27458237}.
CC -!- PTM: Ubiquitinated. {ECO:0000269|PubMed:23746843}.
CC -!- PTM: Acetylated. {ECO:0000269|PubMed:23746843}.
CC -!- PTM: Phosphorylated (PubMed:23746843, PubMed:24726323,
CC PubMed:24726327). Phosphorylation at Tyr-56 prevents interaction with
CC RNF31; dephosphorylation promotes interaction with RNF31 and the LUBAC
CC complex (PubMed:24726323, PubMed:24726327).
CC {ECO:0000269|PubMed:23746843, ECO:0000269|PubMed:24726323,
CC ECO:0000269|PubMed:24726327}.
CC -!- DISEASE: Autoinflammation, panniculitis, and dermatosis syndrome
CC (AIPDS) [MIM:617099]: An autosomal recessive autoinflammatory disorder
CC characterized by neonatal-onset of fever, neutrophilic dermatitis,
CC panniculitis, painful joints, failure to thrive. Patients do not
CC exhibit overt primary immunodeficiency. {ECO:0000269|PubMed:27523608,
CC ECO:0000269|PubMed:27559085}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase C65 family. Otulin subfamily.
CC {ECO:0000305}.
CC -!- CAUTION: The key substrates of OTULIN and where OTULIN acts to limit
CC inflammation have been subject to discussion. According to some
CC reports, OTULIN plays active roles in TNF or NOD2 receptor signaling
CC complexes (RSCs) by directly deubiquitinating proteins in these
CC complexes (PubMed:26997266, PubMed:27523608). A publication also
CC suggested that OTULIN directly mediates deubiquitination of RIPK2
CC (PubMed:23806334). However, a publication reported that OTULIN function
CC is restricted to homeostasis of the LUBAC complex, because it is not
CC stably associated with TNF or NOD2 receptor signaling complexes (RSCs)
CC (PubMed:26670046). The main function of OTULIN in deubiquitinating the
CC LUBAC complex was confirmed by knockin experiments in mouse.
CC {ECO:0000250|UniProtKB:Q3UCV8, ECO:0000269|PubMed:23806334,
CC ECO:0000269|PubMed:26670046, ECO:0000269|PubMed:26997266,
CC ECO:0000269|PubMed:27523608}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH07706.3; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAH15392.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAC03828.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AC010491; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471102; EAX08038.1; -; Genomic_DNA.
DR EMBL; CH471102; EAX08039.1; -; Genomic_DNA.
DR EMBL; BC007706; AAH07706.3; ALT_INIT; mRNA.
DR EMBL; BC015392; AAH15392.2; ALT_INIT; mRNA.
DR EMBL; AK092203; BAC03828.1; ALT_INIT; mRNA.
DR CCDS; CCDS43302.1; -.
DR RefSeq; NP_612357.4; NM_138348.5.
DR RefSeq; XP_011512453.1; XM_011514151.2.
DR RefSeq; XP_011512454.1; XM_011514152.2.
DR PDB; 3ZNV; X-ray; 1.30 A; A=80-352.
DR PDB; 3ZNX; X-ray; 1.35 A; A=80-352.
DR PDB; 3ZNZ; X-ray; 1.90 A; A=80-352.
DR PDB; 4KSJ; X-ray; 1.60 A; A=79-352.
DR PDB; 4KSK; X-ray; 2.40 A; A/B=55-352.
DR PDB; 4KSL; X-ray; 2.83 A; A/B/E/G/I/K/M/O/Q/S/U/W=79-352.
DR PDB; 4OYK; X-ray; 2.00 A; C/D=49-67.
DR PDB; 4P0B; X-ray; 2.70 A; B/D=52-61.
DR PDB; 5OE7; X-ray; 2.95 A; A=80-350.
DR PDB; 6I9C; X-ray; 1.77 A; A=80-345.
DR PDB; 6SAK; X-ray; 2.00 A; A/B=80-352.
DR PDBsum; 3ZNV; -.
DR PDBsum; 3ZNX; -.
DR PDBsum; 3ZNZ; -.
DR PDBsum; 4KSJ; -.
DR PDBsum; 4KSK; -.
DR PDBsum; 4KSL; -.
DR PDBsum; 4OYK; -.
DR PDBsum; 4P0B; -.
DR PDBsum; 5OE7; -.
DR PDBsum; 6I9C; -.
DR PDBsum; 6SAK; -.
DR AlphaFoldDB; Q96BN8; -.
DR SMR; Q96BN8; -.
DR BioGRID; 124684; 79.
DR IntAct; Q96BN8; 21.
DR MINT; Q96BN8; -.
DR STRING; 9606.ENSP00000284274; -.
DR GlyGen; Q96BN8; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q96BN8; -.
DR PhosphoSitePlus; Q96BN8; -.
DR BioMuta; OTULIN; -.
DR DMDM; 118572305; -.
DR EPD; Q96BN8; -.
DR jPOST; Q96BN8; -.
DR MassIVE; Q96BN8; -.
DR MaxQB; Q96BN8; -.
DR PaxDb; Q96BN8; -.
DR PeptideAtlas; Q96BN8; -.
DR PRIDE; Q96BN8; -.
DR ProteomicsDB; 76094; -.
DR Antibodypedia; 56178; 94 antibodies from 21 providers.
DR DNASU; 90268; -.
DR Ensembl; ENST00000284274.5; ENSP00000284274.4; ENSG00000154124.5.
DR GeneID; 90268; -.
DR KEGG; hsa:90268; -.
DR MANE-Select; ENST00000284274.5; ENSP00000284274.4; NM_138348.6; NP_612357.4.
DR UCSC; uc003jfk.4; human.
DR CTD; 90268; -.
DR DisGeNET; 90268; -.
DR GeneCards; OTULIN; -.
DR HGNC; HGNC:25118; OTULIN.
DR HPA; ENSG00000154124; Tissue enhanced (bone).
DR MalaCards; OTULIN; -.
DR MIM; 615712; gene.
DR MIM; 617099; phenotype.
DR neXtProt; NX_Q96BN8; -.
DR OpenTargets; ENSG00000154124; -.
DR Orphanet; 500062; Infantile-onset periodic fever-panniculitis-dermatosis syndrome.
DR PharmGKB; PA142671789; -.
DR VEuPathDB; HostDB:ENSG00000154124; -.
DR eggNOG; ENOG502QTB8; Eukaryota.
DR GeneTree; ENSGT00390000009802; -.
DR HOGENOM; CLU_051856_1_1_1; -.
DR InParanoid; Q96BN8; -.
DR OMA; TDPPRDW; -.
DR OrthoDB; 1416236at2759; -.
DR PhylomeDB; Q96BN8; -.
DR TreeFam; TF328709; -.
DR PathwayCommons; Q96BN8; -.
DR Reactome; R-HSA-5357905; Regulation of TNFR1 signaling.
DR Reactome; R-HSA-8866652; Synthesis of active ubiquitin: roles of E1 and E2 enzymes.
DR SignaLink; Q96BN8; -.
DR BioGRID-ORCS; 90268; 14 hits in 1114 CRISPR screens.
DR ChiTaRS; OTULIN; human.
DR GenomeRNAi; 90268; -.
DR Pharos; Q96BN8; Tbio.
DR PRO; PR:Q96BN8; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; Q96BN8; protein.
DR Bgee; ENSG00000154124; Expressed in buccal mucosa cell and 164 other tissues.
DR ExpressionAtlas; Q96BN8; baseline and differential.
DR Genevisible; Q96BN8; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0071797; C:LUBAC complex; IEA:Ensembl.
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; IDA: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; IDA:UniProtKB.
DR GO; GO:0070431; P:nucleotide-binding oligomerization domain containing 2 signaling pathway; IMP:UniProtKB.
DR GO; GO:1990108; P:protein linear deubiquitination; IDA:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; TAS:Reactome.
DR GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; ISS:UniProtKB.
DR GO; GO:0010803; P:regulation of tumor necrosis factor-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0002040; P:sprouting angiogenesis; ISS:UniProtKB.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR InterPro; IPR023235; FAM105.
DR InterPro; IPR023237; Otulin.
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 3D-structure; Acetylation; Angiogenesis; Cytoplasm; Disease variant;
KW Hydrolase; Immunity; Innate immunity; Phosphoprotein; Protease;
KW Reference proteome; Thiol protease; Ubl conjugation;
KW Ubl conjugation pathway; Wnt signaling pathway.
FT CHAIN 1..352
FT /note="Ubiquitin thioesterase otulin"
FT /id="PRO_0000261637"
FT DOMAIN 118..346
FT /note="OTU"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00139"
FT REGION 1..48
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 95..96
FT /note="Linear diubiquitin binding"
FT /evidence="ECO:0000269|PubMed:23708998,
FT ECO:0000269|PubMed:23746843, ECO:0007744|PDB:3ZNZ,
FT ECO:0007744|PDB:4KSL"
FT REGION 124..126
FT /note="Linear diubiquitin binding"
FT /evidence="ECO:0000269|PubMed:23708998,
FT ECO:0000269|PubMed:23746843, ECO:0007744|PDB:3ZNZ,
FT ECO:0007744|PDB:4KSL"
FT REGION 255..259
FT /note="Linear diubiquitin binding"
FT /evidence="ECO:0000269|PubMed:23708998,
FT ECO:0000269|PubMed:23746843, ECO:0007744|PDB:3ZNZ,
FT ECO:0007744|PDB:4KSK, ECO:0007744|PDB:4KSL"
FT REGION 283..289
FT /note="Linear diubiquitin binding"
FT /evidence="ECO:0000269|PubMed:23708998,
FT ECO:0000269|PubMed:23746843, ECO:0007744|PDB:3ZNZ,
FT ECO:0007744|PDB:4KSK, ECO:0007744|PDB:4KSL"
FT REGION 336..338
FT /note="Linear diubiquitin binding"
FT /evidence="ECO:0000269|PubMed:23708998,
FT ECO:0000269|PubMed:23746843, ECO:0007744|PDB:3ZNZ,
FT ECO:0007744|PDB:4KSL"
FT MOTIF 52..57
FT /note="PIM motif"
FT /evidence="ECO:0000269|PubMed:24726323,
FT ECO:0000269|PubMed:24726327, ECO:0000269|PubMed:27458237"
FT ACT_SITE 126
FT /evidence="ECO:0000269|PubMed:23708998,
FT ECO:0000269|PubMed:23746843, ECO:0007744|PDB:3ZNZ,
FT ECO:0007744|PDB:4KSL"
FT ACT_SITE 129
FT /note="Nucleophile"
FT /evidence="ECO:0000269|PubMed:23708998,
FT ECO:0000269|PubMed:23746843, ECO:0000269|PubMed:24726327,
FT ECO:0007744|PDB:3ZNZ, ECO:0007744|PDB:4KSL"
FT ACT_SITE 339
FT /evidence="ECO:0000269|PubMed:23708998,
FT ECO:0000269|PubMed:23746843, ECO:0007744|PDB:3ZNZ,
FT ECO:0007744|PDB:4KSL"
FT SITE 314
FT /note="Linear diubiquitin binding"
FT /evidence="ECO:0000269|PubMed:23708998,
FT ECO:0000269|PubMed:23746843, ECO:0007744|PDB:3ZNZ,
FT ECO:0007744|PDB:4KSK, ECO:0007744|PDB:4KSL"
FT MOD_RES 56
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:24726323,
FT ECO:0000269|PubMed:24726327"
FT VARIANT 155
FT /note="M -> L (in dbSNP:rs11953822)"
FT /id="VAR_053819"
FT VARIANT 227
FT /note="S -> N (in dbSNP:rs9312870)"
FT /id="VAR_029469"
FT VARIANT 244
FT /note="Y -> C (in AIPDS; slightly impaired ability to
FT mediate deubiquitination of linear polyubiquitin chains;
FT does not affect ability to interact with RNF31;
FT dbSNP:rs886037887)"
FT /evidence="ECO:0000269|PubMed:27559085"
FT /id="VAR_076865"
FT VARIANT 272
FT /note="L -> P (in AIPDS; decreased stability; impaired
FT ability to mediate deubiquitination of linear polyubiquitin
FT chains; increased NF-kappa-B signaling; does not affect
FT ability to interact with RNF31; dbSNP:rs886037885)"
FT /evidence="ECO:0000269|PubMed:27523608,
FT ECO:0000269|PubMed:27559085"
FT /id="VAR_076866"
FT VARIANT 311
FT /note="N -> S (in dbSNP:rs9312870)"
FT /id="VAR_053820"
FT MUTAGEN 54
FT /note="D->A: Reduced interaction with RNF31."
FT /evidence="ECO:0000269|PubMed:24726323"
FT MUTAGEN 55
FT /note="M->D: Abolished interaction with RNF31."
FT /evidence="ECO:0000269|PubMed:24726323"
FT MUTAGEN 56
FT /note="Y->A,D: Abolished interaction with RNF31."
FT /evidence="ECO:0000269|PubMed:24726323,
FT ECO:0000269|PubMed:24726327, ECO:0000269|PubMed:27458237"
FT MUTAGEN 56
FT /note="Y->E,F,W: Strongly reduced interaction with RNF31."
FT /evidence="ECO:0000269|PubMed:24726323,
FT ECO:0000269|PubMed:24726327"
FT MUTAGEN 91
FT /note="Y->F: Results in strong reduction of kcat while not
FT affecting KM."
FT /evidence="ECO:0000269|PubMed:23746843"
FT MUTAGEN 96
FT /note="W->A: Decreased activity toward linear ubiquitin."
FT /evidence="ECO:0000269|PubMed:23746843,
FT ECO:0000269|PubMed:23806334"
FT MUTAGEN 100..102
FT /note="TQK->AAA: Decreased activity toward linear
FT ubiquitin."
FT /evidence="ECO:0000269|PubMed:23746843"
FT MUTAGEN 129
FT /note="C->A,S: Abolishes deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:23708998,
FT ECO:0000269|PubMed:23746843, ECO:0000269|PubMed:23806334,
FT ECO:0000269|PubMed:24726327, ECO:0000269|PubMed:28919039"
FT MUTAGEN 259
FT /note="L->E: Decreased affinity for linear diubiquitin."
FT /evidence="ECO:0000269|PubMed:23746843"
FT MUTAGEN 314
FT /note="E->R: Decreased affinity for linear diubiquitin."
FT /evidence="ECO:0000269|PubMed:23746843"
FT MUTAGEN 336
FT /note="D->A: Stabilizes H-339 in the active conformation,
FT generating a more reactive enzyme."
FT /evidence="ECO:0000269|PubMed:23746843"
FT MUTAGEN 339
FT /note="H->A: Impaired deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:23746843"
FT MUTAGEN 341
FT /note="N->A: Abolishes deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:23746843"
FT MUTAGEN 341
FT /note="N->D: Stabilizes H-339 in the active conformation,
FT generating a more reactive enzyme."
FT /evidence="ECO:0000269|PubMed:23746843"
FT CONFLICT 211
FT /note="R -> G (in Ref. 4; BAC03828)"
FT /evidence="ECO:0000305"
FT STRAND 55..57
FT /evidence="ECO:0007829|PDB:4OYK"
FT HELIX 59..63
FT /evidence="ECO:0007829|PDB:4OYK"
FT HELIX 88..95
FT /evidence="ECO:0007829|PDB:3ZNV"
FT HELIX 101..114
FT /evidence="ECO:0007829|PDB:3ZNV"
FT STRAND 118..121
FT /evidence="ECO:0007829|PDB:3ZNV"
FT HELIX 129..140
FT /evidence="ECO:0007829|PDB:3ZNV"
FT HELIX 147..150
FT /evidence="ECO:0007829|PDB:3ZNV"
FT HELIX 153..164
FT /evidence="ECO:0007829|PDB:3ZNV"
FT HELIX 166..170
FT /evidence="ECO:0007829|PDB:3ZNV"
FT HELIX 181..183
FT /evidence="ECO:0007829|PDB:6SAK"
FT HELIX 184..204
FT /evidence="ECO:0007829|PDB:3ZNV"
FT HELIX 208..218
FT /evidence="ECO:0007829|PDB:3ZNV"
FT STRAND 220..222
FT /evidence="ECO:0007829|PDB:3ZNV"
FT HELIX 223..248
FT /evidence="ECO:0007829|PDB:3ZNV"
FT HELIX 255..262
FT /evidence="ECO:0007829|PDB:3ZNV"
FT STRAND 263..265
FT /evidence="ECO:0007829|PDB:4KSL"
FT HELIX 269..275
FT /evidence="ECO:0007829|PDB:3ZNV"
FT HELIX 277..279
FT /evidence="ECO:0007829|PDB:3ZNV"
FT TURN 280..282
FT /evidence="ECO:0007829|PDB:3ZNV"
FT HELIX 288..298
FT /evidence="ECO:0007829|PDB:3ZNV"
FT STRAND 301..306
FT /evidence="ECO:0007829|PDB:3ZNV"
FT HELIX 307..309
FT /evidence="ECO:0007829|PDB:3ZNV"
FT HELIX 313..315
FT /evidence="ECO:0007829|PDB:3ZNV"
FT STRAND 316..322
FT /evidence="ECO:0007829|PDB:3ZNV"
FT STRAND 329..336
FT /evidence="ECO:0007829|PDB:3ZNV"
FT STRAND 339..344
FT /evidence="ECO:0007829|PDB:3ZNV"
FT HELIX 346..348
FT /evidence="ECO:0007829|PDB:3ZNZ"
SQ SEQUENCE 352 AA; 40263 MW; 65071FF7B427C2FA CRC64;
MSRGTMPQPE AWPGASCAET PAREAAATAR DGGKAAASGQ PRPEMQCPAE HEEDMYRAAD
EIEKEKELLI HERGASEPRL SVAPEMDIMD YCKKEWRGNT QKATCMKMGY EEVSQKFTSI
RRVRGDNYCA LRATLFQAMS QAVGLPPWLQ DPELMLLPEK LISKYNWIKQ WKLGLKFDGK
NEDLVDKIKE SLTLLRKKWA GLAEMRTAEA RQIACDELFT NEAEEYSLYE AVKFLMLNRA
IELYNDKEKG KEVPFFSVLL FARDTSNDPG QLLRNHLNQV GHTGGLEQVE MFLLAYAVRH
TIQVYRLSKY NTEEFITVYP TDPPKDWPVV TLIAEDDRHY NIPVRVCEET SL
