ID CYLD_MOUSE Reviewed; 952 AA. AC Q80TQ2; Q80VB3; Q8BXZ3; Q8BYL9; Q8CGB0; DT 16-AUG-2004, integrated into UniProtKB/Swiss-Prot. DT 16-AUG-2004, sequence version 2. DT 27-MAR-2024, entry version 177. DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase CYLD; DE EC=3.4.19.12 {ECO:0000269|PubMed:32424362}; DE AltName: Full=Deubiquitinating enzyme CYLD; DE AltName: Full=Ubiquitin thioesterase CYLD; DE AltName: Full=Ubiquitin-specific-processing protease CYLD; GN Name=Cyld; Synonyms=Cyld1, Kiaa0849; 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] (ISOFORM 2). RC TISSUE=Brain; RX PubMed=12693553; DOI=10.1093/dnares/10.1.35; RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Aizawa H., Yuasa S., RA Nakajima D., Nagase T., Ohara O., Koga H.; RT "Prediction of the coding sequences of mouse homologues of KIAA gene: II. RT The complete nucleotide sequences of 400 mouse KIAA-homologous cDNAs RT identified by screening of terminal sequences of cDNA clones randomly RT sampled from size-fractionated libraries."; RL DNA Res. 10:35-48(2003). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND NUCLEOTIDE SEQUENCE RP [LARGE SCALE MRNA] OF 1-620 (ISOFORM 1). RC STRAIN=C57BL/6J; TISSUE=Cerebellum, and Hypothalamus; 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 [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC STRAIN=FVB/N; TISSUE=Mammary gland; 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, DISRUPTION PHENOTYPE, INTERACTION WITH BCL3, AND SUBCELLULAR RP LOCATION. RX PubMed=16713561; DOI=10.1016/j.cell.2006.03.041; RA Massoumi R., Chmielarska K., Hennecke K., Pfeifer A., Fassler R.; RT "Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF- RT kappaB signaling."; RL Cell 125:665-677(2006). RN [5] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=16501569; DOI=10.1038/ni1315; RA Reiley W.W., Zhang M., Jin W., Losiewicz M., Donohue K.B., Norbury C.C., RA Sun S.C.; RT "Regulation of T cell development by the deubiquitinating enzyme CYLD."; RL Nat. Immunol. 7:411-417(2006). RN [6] RP FUNCTION, INTERACTION WITH MAP3K7, AND DISRUPTION PHENOTYPE. RX PubMed=17548520; DOI=10.1084/jem.20062694; RA Reiley W.W., Jin W., Lee A.J., Wright A., Wu X., Tewalt E.F., Leonard T.O., RA Norbury C.C., Fitzpatrick L., Zhang M., Sun S.C.; RT "Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent RT kinase Tak1 and prevents abnormal T cell responses."; RL J. Exp. Med. 204:1475-1485(2007). RN [7] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=18643924; DOI=10.1111/j.1462-5822.2008.01204.x; RA Lim J.H., Ha U.H., Woo C.H., Xu H., Li J.D.; RT "CYLD is a crucial negative regulator of innate immune response in RT Escherichia coli pneumonia."; RL Cell. Microbiol. 10:2247-2256(2008). RN [8] RP DISRUPTION PHENOTYPE, FUNCTION, INTERACTION WITH SQSTM1, IDENTIFICATION IN RP A COMPLEX WITH TRAF6 AND SQSTM1, AND INDUCTION. RX PubMed=18382763; DOI=10.1172/jci34257; RA Jin W., Chang M., Paul E.M., Babu G., Lee A.J., Reiley W., Wright A., RA Zhang M., You J., Sun S.C.; RT "Deubiquitinating enzyme CYLD negatively regulates RANK signaling and RT osteoclastogenesis in mice."; RL J. Clin. Invest. 118:1858-1866(2008). RN [9] RP FUNCTION. RX PubMed=20194890; DOI=10.1182/blood-2009-10-248526; RA Gao J., Sun L., Huo L., Liu M., Li D., Zhou J.; RT "CYLD regulates angiogenesis by mediating vascular endothelial cell RT migration."; RL Blood 115:4130-4137(2010). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-414, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain, and Kidney; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [11] RP FUNCTION, INTERACTION WITH HDAC6, BCL3 AND MICROTUBULES, AND SUBCELLULAR RP LOCATION. RX PubMed=19893491; DOI=10.1038/emboj.2009.317; RA Wickstrom S.A., Masoumi K.C., Khochbin S., Fassler R., Massoumi R.; RT "CYLD negatively regulates cell-cycle progression by inactivating HDAC6 and RT increasing the levels of acetylated tubulin."; RL EMBO J. 29:131-144(2010). RN [12] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=25134987; DOI=10.1038/ncomms5585; RA Eguether T., Ermolaeva M.A., Zhao Y., Bonnet M.C., Jain A., Pasparakis M., RA Courtois G., Tassin A.M.; RT "The deubiquitinating enzyme CYLD controls apical docking of basal bodies RT in ciliated epithelial cells."; RL Nat. Commun. 5:4585-4585(2014). RN [13] RP FUNCTION. RX PubMed=28701375; DOI=10.1101/gad.299776.117; RA Wei R., Xu L.W., Liu J., Li Y., Zhang P., Shan B., Lu X., Qian L., Wu Z., RA Dong K., Zhu H., Pan L., Yuan J., Pan H.; RT "SPATA2 regulates the activation of RIPK1 by modulating linear RT ubiquitination."; RL Genes Dev. 31:1162-1176(2017). RN [14] RP FUNCTION, UBIQUITINATION, AND DISRUPTION PHENOTYPE. RX PubMed=29291351; DOI=10.1038/nm.4461; RA Ji Y.X., Huang Z., Yang X., Wang X., Zhao L.P., Wang P.X., Zhang X.J., RA Alves-Bezerra M., Cai L., Zhang P., Lu Y.X., Bai L., Gao M.M., Zhao H., RA Tian S., Wang Y., Huang Z.X., Zhu X.Y., Zhang Y., Gong J., She Z.G., Li F., RA Cohen D.E., Li H.; RT "The deubiquitinating enzyme cylindromatosis mitigates nonalcoholic RT steatohepatitis."; RL Nat. Med. 24:213-223(2018). RN [15] RP FUNCTION, AND MUTAGENESIS OF ASP-677 AND MET-715. RX PubMed=32185393; DOI=10.1093/brain/awaa039; RA Dobson-Stone C., Hallupp M., Shahheydari H., Ragagnin A.M.G., RA Chatterton Z., Carew-Jones F., Shepherd C.E., Stefen H., Paric E., Fath T., RA Thompson E.M., Blumbergs P., Short C.L., Field C.D., Panegyres P.K., RA Hecker J., Nicholson G., Shaw A.D., Fullerton J.M., Luty A.A., RA Schofield P.R., Brooks W.S., Rajan N., Bennett M.F., Bahlo M., RA Landers J.E., Piguet O., Hodges J.R., Halliday G.M., Topp S.D., Smith B.N., RA Shaw C.E., McCann E., Fifita J.A., Williams K.L., Atkin J.D., Blair I.P., RA Kwok J.B.; RT "CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral RT sclerosis."; RL Brain 143:783-799(2020). RN [16] RP FUNCTION, CATALYTIC ACTIVITY, DISRUPTION PHENOTYPE, ACTIVE SITE, AND RP MUTAGENESIS OF CYS-597. RX PubMed=32424362; DOI=10.1038/s41590-020-0681-x; RA Mukherjee S., Kumar R., Tsakem Lenou E., Basrur V., Kontoyiannis D.L., RA Ioakeimidis F., Mosialos G., Theiss A.L., Flavell R.A., Venuprasad K.; RT "Deubiquitination of NLRP6 inflammasome by Cyld critically regulates RT intestinal inflammation."; RL Nat. Immunol. 21:626-635(2020). CC -!- FUNCTION: Deubiquitinase that specifically cleaves 'Lys-63'- and linear CC 'Met-1'-linked polyubiquitin chains and is involved in NF-kappa-B CC activation and TNF-alpha-induced necroptosis (PubMed:17548520, CC PubMed:28701375, PubMed:29291351, PubMed:32185393, PubMed:32424362). CC Negatively regulates NF-kappa-B activation by deubiquitinating upstream CC signaling factors (PubMed:16713561). Contributes to the regulation of CC cell survival, proliferation and differentiation via its effects on NF- CC kappa-B activation (PubMed:16713561). Negative regulator of Wnt CC signaling. Inhibits HDAC6 and thereby promotes acetylation of alpha- CC tubulin and stabilization of microtubules (PubMed:19893491). Plays a CC role in the regulation of microtubule dynamics, and thereby contributes CC to the regulation of cell proliferation, cell polarization, cell CC migration, and angiogenesis (PubMed:16713561, PubMed:20194890, CC PubMed:19893491). Required for normal cell cycle progress and normal CC cytokinesis (PubMed:19893491). Inhibits nuclear translocation of NF- CC kappa-B (By similarity). Plays a role in the regulation of inflammation CC and the innate immune response, via its effects on NF-kappa-B CC activation (By similarity). Dispensable for the maturation of CC intrathymic natural killer cells, but required for the continued CC survival of immature natural killer cells (PubMed:16501569, CC PubMed:18643924). Negatively regulates TNFRSF11A signaling and CC osteoclastogenesis (PubMed:18382763). Involved in the regulation of CC ciliogenesis, allowing ciliary basal bodies to migrate and dock to the CC plasma membrane; this process does not depend on NF-kappa-B activation CC (PubMed:25134987). Ability to remove linear ('Met-1'-linked) CC polyubiquitin chains regulates innate immunity and TNF-alpha-induced CC necroptosis: recruited to the LUBAC complex via interaction with SPATA2 CC and restricts linear polyubiquitin formation on target proteins CC (PubMed:28701375). Regulates innate immunity by restricting linear CC polyubiquitin formation on RIPK2 in response to NOD2 stimulation (By CC similarity). Involved in TNF-alpha-induced necroptosis by removing CC linear ('Met-1'-linked) polyubiquitin chains from RIPK1, thereby CC regulating the kinase activity of RIPK1 (PubMed:28701375). Negatively CC regulates intestinal inflammation by removing 'Lys-63' linked CC polyubiquitin chain of NLRP6, thereby reducing the interaction between CC NLRP6 and PYCARD/ASC and formation of the NLRP6 inflammasome CC (PubMed:32424362). Removes 'Lys-63' linked polyubiquitin chain of CC MAP3K7, which inhibits phosphorylation and blocks downstream activation CC of the JNK-p38 kinase cascades (PubMed:17548520, PubMed:29291351). CC Removes also 'Lys-63'-linked polyubiquitin chains of MAP3K1 and CC MA3P3K3, which inhibit their interaction with MAP2K1 and MAP2K2 (By CC similarity). {ECO:0000250|UniProtKB:Q9NQC7, CC ECO:0000269|PubMed:16501569, ECO:0000269|PubMed:16713561, CC ECO:0000269|PubMed:17548520, ECO:0000269|PubMed:18382763, CC ECO:0000269|PubMed:18643924, ECO:0000269|PubMed:19893491, CC ECO:0000269|PubMed:20194890, ECO:0000269|PubMed:25134987, CC ECO:0000269|PubMed:28701375, ECO:0000269|PubMed:29291351, CC ECO:0000269|PubMed:32185393, ECO:0000269|PubMed:32424362}. 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:32424362}; CC -!- SUBUNIT: Interacts (via CAP-Gly domain) with IKBKG/NEMO (via proline- CC rich C-terminal region) (By similarity). Interacts with TRAF2 and TRIP CC (By similarity). Interacts with PLK1, DVL1, DVL3, MAVS, TBK1, IKKE and CC RIGI (By similarity). Interacts (via CAP-Gly domain) with microtubules CC (PubMed:19893491). Interacts with HDAC6 and BCL3 (PubMed:16713561, CC PubMed:19893491). Interacts with MAP3K7 (PubMed:17548520). Identified CC in a complex with TRAF6 and SQSTM1 (PubMed:18382763). Interacts with CC OPTN and SQSTM1 (By similarity). Interacts with CEP350 (By similarity). CC Interacts with RNF31; the interaction is indirect and is mediated via CC SPATA2 (By similarity). Interacts with SPATA2 (via the PUB domain); the CC interaction is direct and recruits CYLD to the LUBAC complex, thereby CC regulating TNF-alpha-induced necroptosis (By similarity). CC {ECO:0000250|UniProtKB:Q9NQC7, ECO:0000269|PubMed:16713561, CC ECO:0000269|PubMed:17548520, ECO:0000269|PubMed:18382763, CC ECO:0000269|PubMed:19893491}. CC -!- INTERACTION: CC Q80TQ2; Q9Z2F6: Bcl3; NbExp=5; IntAct=EBI-943859, EBI-943884; CC Q80TQ2; Q9Z2V5: Hdac6; NbExp=3; IntAct=EBI-943859, EBI-1009256; CC Q80TQ2; Q8C863: Itch; NbExp=2; IntAct=EBI-943859, EBI-851782; CC Q80TQ2; P68369: Tuba1a; NbExp=5; IntAct=EBI-943859, EBI-400542; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, perinuclear region. CC Cytoplasm, cytoskeleton. Cell membrane {ECO:0000250|UniProtKB:Q9NQC7}; CC Peripheral membrane protein {ECO:0000250|UniProtKB:Q9NQC7}; Cytoplasmic CC side {ECO:0000250|UniProtKB:Q9NQC7}. Cytoplasm, cytoskeleton, CC microtubule organizing center, centrosome CC {ECO:0000250|UniProtKB:Q9NQC7}. Cytoplasm, cytoskeleton, spindle CC {ECO:0000250|UniProtKB:Q9NQC7}. Cytoplasm, cytoskeleton, cilium basal CC body {ECO:0000269|PubMed:25134987}. Note=Detected at the microtubule CC cytoskeleton during interphase (By similarity). Detected at the midbody CC during telophase (By similarity). During metaphase, it remains CC localized to the centrosome but is also present along the spindle (By CC similarity). {ECO:0000250|UniProtKB:Q9NQC7, CC ECO:0000269|PubMed:25134987}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=2; CC IsoId=Q80TQ2-1; Sequence=Displayed; CC Name=1; CC IsoId=Q80TQ2-2; Sequence=VSP_011278; CC Name=3; CC IsoId=Q80TQ2-3; Sequence=VSP_011279, VSP_011280; CC -!- INDUCTION: Up-regulated by TNFRSF11A. {ECO:0000269|PubMed:18382763}. CC -!- PTM: Phosphorylated on several serine residues by IKKA and/or IKKB in CC response to immune stimuli. Phosphorylation requires IKBKG. CC Phosphorylation abolishes TRAF2 deubiquitination, interferes with the CC activation of Jun kinases, and strongly reduces CD40-dependent gene CC activation by NF-kappa-B (By similarity). CC {ECO:0000250|UniProtKB:Q9NQC7}. CC -!- PTM: Ubiquitinated. Polyubiquitinated in hepatocytes treated with CC palmitic acid. Ubiquitination is mediated by E3 ligase TRIM47 and leads CC to proteasomal degradation. {ECO:0000269|PubMed:29291351}. CC -!- DISRUPTION PHENOTYPE: No obvious phenotype, but mice are highly CC susceptible to carcinogens and are prone to chemically induced skin CC tumors (PubMed:16501569, PubMed:16713561, PubMed:17548520, CC PubMed:18382763, PubMed:18643924). The number of natural killer T-cells CC is much reduced (PubMed:16501569, PubMed:16713561, PubMed:17548520, CC PubMed:18382763, PubMed:18643924). Animals are highly susceptible to CC bacteria-induced pneumonia, due to an over active innate immune CC response (PubMed:16501569, PubMed:16713561, PubMed:17548520, CC PubMed:18382763, PubMed:18643924). Mice are more susceptible to CC C.rodentium infection, leading to severe inflammation in the intestine CC (PubMed:32424362). Animals spontaneously develop colonic inflammation, CC due to constitutive expression of several pro-inflammatory genes in the CC colon (PubMed:16501569, PubMed:16713561, PubMed:17548520, CC PubMed:18382763, PubMed:18643924). Animals exhibit abnormal osteoclast CC differentiation, leading to osteoporosis (PubMed:16501569, CC PubMed:16713561, PubMed:17548520, PubMed:18382763, PubMed:18643924). CC Hepatocyte-specific knockout mice do not exhibit any liver-related CC pathological phenotype under unstressed conditions (PubMed:29291351). CC In response to a 24-week high fat dier, they exhibit higher body and CC liver weight as well as reduced glucose tolerance and insulin CC resistance compared to controls (PubMed:29291351). They also show a CC considerable inflammatory response, including elevation of cytokine and CC chemokine concentrations in serum and mRNA expression in liver CC (PubMed:29291351). {ECO:0000269|PubMed:16501569, CC ECO:0000269|PubMed:16713561, ECO:0000269|PubMed:17548520, CC ECO:0000269|PubMed:18382763, ECO:0000269|PubMed:18643924, CC ECO:0000269|PubMed:29291351, ECO:0000269|PubMed:32424362}. CC -!- SIMILARITY: Belongs to the peptidase C19 family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAC65671.1; Type=Erroneous initiation; Note=Extended 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; AK122389; BAC65671.1; ALT_INIT; mRNA. DR EMBL; AK039054; BAC30222.1; -; mRNA. DR EMBL; AK042764; BAC31357.1; -; mRNA. DR EMBL; BC042438; AAH42438.1; -; mRNA. DR EMBL; BC049879; AAH49879.1; -; mRNA. DR CCDS; CCDS22513.1; -. [Q80TQ2-1] DR CCDS; CCDS52633.1; -. [Q80TQ2-2] DR RefSeq; NP_001121642.1; NM_001128170.2. [Q80TQ2-2] DR RefSeq; NP_001121643.1; NM_001128171.2. [Q80TQ2-1] DR RefSeq; NP_775545.1; NM_173369.3. [Q80TQ2-1] DR RefSeq; XP_006531477.1; XM_006531414.1. [Q80TQ2-2] DR RefSeq; XP_006531478.1; XM_006531415.1. [Q80TQ2-2] DR RefSeq; XP_006531479.1; XM_006531416.3. [Q80TQ2-2] DR RefSeq; XP_006531480.1; XM_006531417.2. [Q80TQ2-2] DR RefSeq; XP_006531481.1; XM_006531418.2. [Q80TQ2-2] DR RefSeq; XP_011246825.1; XM_011248523.2. [Q80TQ2-2] DR RefSeq; XP_011246826.1; XM_011248524.1. [Q80TQ2-2] DR RefSeq; XP_011246827.1; XM_011248525.2. [Q80TQ2-2] DR RefSeq; XP_017168478.1; XM_017312989.1. DR AlphaFoldDB; Q80TQ2; -. DR SMR; Q80TQ2; -. DR BioGRID; 216612; 28. DR DIP; DIP-35656N; -. DR IntAct; Q80TQ2; 8. DR MINT; Q80TQ2; -. DR STRING; 10090.ENSMUSP00000147654; -. DR MEROPS; C67.001; -. DR GlyGen; Q80TQ2; 2 sites, 1 O-linked glycan (2 sites). DR iPTMnet; Q80TQ2; -. DR PhosphoSitePlus; Q80TQ2; -. DR SwissPalm; Q80TQ2; -. DR EPD; Q80TQ2; -. DR MaxQB; Q80TQ2; -. DR PaxDb; 10090-ENSMUSP00000039834; -. DR PeptideAtlas; Q80TQ2; -. DR ProteomicsDB; 279252; -. [Q80TQ2-1] DR ProteomicsDB; 279253; -. [Q80TQ2-2] DR ProteomicsDB; 279254; -. [Q80TQ2-3] DR Pumba; Q80TQ2; -. DR Antibodypedia; 3193; 375 antibodies from 39 providers. DR DNASU; 74256; -. DR Ensembl; ENSMUST00000098519.11; ENSMUSP00000096119.5; ENSMUSG00000036712.16. [Q80TQ2-2] DR Ensembl; ENSMUST00000109626.4; ENSMUSP00000105254.4; ENSMUSG00000036712.16. [Q80TQ2-1] DR Ensembl; ENSMUST00000209532.2; ENSMUSP00000147654.2; ENSMUSG00000036712.16. [Q80TQ2-2] DR Ensembl; ENSMUST00000209559.2; ENSMUSP00000147426.2; ENSMUSG00000036712.16. [Q80TQ2-1] DR Ensembl; ENSMUST00000211554.2; ENSMUSP00000148037.2; ENSMUSG00000036712.16. [Q80TQ2-1] DR GeneID; 74256; -. DR KEGG; mmu:74256; -. DR UCSC; uc009mrt.3; mouse. [Q80TQ2-1] DR UCSC; uc033jgq.1; mouse. [Q80TQ2-3] DR UCSC; uc033jgr.1; mouse. [Q80TQ2-2] DR AGR; MGI:1921506; -. DR CTD; 1540; -. DR MGI; MGI:1921506; Cyld. DR VEuPathDB; HostDB:ENSMUSG00000036712; -. DR eggNOG; KOG3556; Eukaryota. DR GeneTree; ENSGT00390000018123; -. DR HOGENOM; CLU_003910_0_0_1; -. DR InParanoid; Q80TQ2; -. DR OMA; SPWYIDE; -. DR OrthoDB; 5397179at2759; -. DR PhylomeDB; Q80TQ2; -. DR BRENDA; 3.4.19.12; 3474. DR Reactome; R-MMU-168638; NOD1/2 Signaling Pathway. DR Reactome; R-MMU-5357786; TNFR1-induced proapoptotic signaling. DR Reactome; R-MMU-5357905; Regulation of TNFR1 signaling. DR Reactome; R-MMU-5357956; TNFR1-induced NF-kappa-B signaling pathway. DR Reactome; R-MMU-5689880; Ub-specific processing proteases. DR Reactome; R-MMU-936440; Negative regulators of DDX58/IFIH1 signaling. DR BioGRID-ORCS; 74256; 3 hits in 81 CRISPR screens. DR ChiTaRS; Cyld; mouse. DR PRO; PR:Q80TQ2; -. DR Proteomes; UP000000589; Chromosome 8. DR RNAct; Q80TQ2; Protein. DR Bgee; ENSMUSG00000036712; Expressed in caudate-putamen and 235 other cell types or tissues. DR ExpressionAtlas; Q80TQ2; baseline and differential. DR GO; GO:0005813; C:centrosome; ISS:UniProtKB. DR GO; GO:0036064; C:ciliary basal body; IDA:UniProtKB. DR GO; GO:0097542; C:ciliary tip; IDA:UniProtKB. DR GO; GO:0005881; C:cytoplasmic microtubule; IEA:Ensembl. DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; IEA:Ensembl. DR GO; GO:0005829; C:cytosol; ISS:UniProtKB. DR GO; GO:0030496; C:midbody; IEA:Ensembl. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0005819; C:spindle; ISS:UniProtKB. DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB. DR GO; GO:1990380; F:K48-linked deubiquitinase activity; IDA:MGI. DR GO; GO:0061578; F:K63-linked deubiquitinase activity; IDA:UniProtKB. DR GO; GO:0061815; F:Met1-linked polyubiquitin deubiquitinase activity; ISO:MGI. DR GO; GO:0070064; F:proline-rich region binding; ISO:MGI. DR GO; GO:0019901; F:protein kinase binding; ISO:MGI. DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB. DR GO; GO:0043369; P:CD4-positive or CD8-positive, alpha-beta T cell lineage commitment; IMP:MGI. DR GO; GO:0048872; P:homeostasis of number of cells; IMP:MGI. DR GO; GO:0045087; P:innate immune response; ISS:UniProtKB. DR GO; GO:0070266; P:necroptotic process; IMP:MGI. DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; ISS:UniProtKB. DR GO; GO:0050728; P:negative regulation of inflammatory response; IMP:UniProtKB. DR GO; GO:2000493; P:negative regulation of interleukin-18-mediated signaling pathway; IMP:UniProtKB. DR GO; GO:0046329; P:negative regulation of JNK cascade; IDA:UniProtKB. DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; ISS:UniProtKB. DR GO; GO:1901223; P:negative regulation of non-canonical NF-kappaB signal transduction; ISS:UniProtKB. DR GO; GO:1903753; P:negative regulation of p38MAPK cascade; IDA:UniProtKB. DR GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; ISO:MGI. DR GO; GO:1903829; P:positive regulation of protein localization; IDA:MGI. DR GO; GO:0045582; P:positive regulation of T cell differentiation; IMP:MGI. DR GO; GO:0050862; P:positive regulation of T cell receptor signaling pathway; IMP:MGI. DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB. DR GO; GO:0070536; P:protein K63-linked deubiquitination; IDA:UniProtKB. DR GO; GO:1990108; P:protein linear deubiquitination; IDA:UniProtKB. DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW. DR GO; GO:0045577; P:regulation of B cell differentiation; IMP:MGI. DR GO; GO:1902017; P:regulation of cilium assembly; IMP:UniProtKB. DR GO; GO:0050727; P:regulation of inflammatory response; ISS:UniProtKB. DR GO; GO:2001242; P:regulation of intrinsic apoptotic signaling pathway; ISO:MGI. DR GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; ISO:MGI. DR GO; GO:0007346; P:regulation of mitotic cell cycle; ISO:MGI. DR GO; GO:0060544; P:regulation of necroptotic process; IDA:UniProtKB. DR GO; GO:0050856; P:regulation of T cell receptor signaling pathway; ISO:MGI. DR GO; GO:0010803; P:regulation of tumor necrosis factor-mediated signaling pathway; IDA:UniProtKB. DR GO; GO:1901026; P:ripoptosome assembly involved in necroptotic process; IMP:MGI. DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW. DR CDD; cd02670; Peptidase_C19N; 1. DR Gene3D; 2.30.30.190; CAP Gly-rich-like domain; 3. DR Gene3D; 3.90.70.10; Cysteine proteinases; 1. DR InterPro; IPR036859; CAP-Gly_dom_sf. DR InterPro; IPR000938; CAP-Gly_domain. DR InterPro; IPR038765; Papain-like_cys_pep_sf. DR InterPro; IPR001394; Peptidase_C19_UCH. DR InterPro; IPR018200; USP_CS. DR InterPro; IPR028889; USP_dom. DR PANTHER; PTHR11830; 40S RIBOSOMAL PROTEIN S3A; 1. DR PANTHER; PTHR11830:SF15; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE CYLD; 1. DR Pfam; PF01302; CAP_GLY; 2. DR Pfam; PF16607; CYLD_phos_site; 1. DR Pfam; PF00443; UCH; 1. DR SMART; SM01052; CAP_GLY; 3. DR SUPFAM; SSF74924; Cap-Gly domain; 3. DR SUPFAM; SSF54001; Cysteine proteinases; 1. DR PROSITE; PS00845; CAP_GLY_1; 1. DR PROSITE; PS50245; CAP_GLY_2; 2. DR PROSITE; PS00972; USP_1; 1. DR PROSITE; PS50235; USP_3; 1. DR Genevisible; Q80TQ2; MM. PE 1: Evidence at protein level; KW Alternative splicing; Cell membrane; Cell projection; Cytoplasm; KW Cytoskeleton; Hydrolase; Immunity; Innate immunity; Membrane; KW Metal-binding; Microtubule; Phosphoprotein; Protease; Reference proteome; KW Repeat; Thiol protease; Ubl conjugation; Ubl conjugation pathway; KW Wnt signaling pathway; Zinc. FT CHAIN 1..952 FT /note="Ubiquitin carboxyl-terminal hydrolase CYLD" FT /id="PRO_0000080699" FT DOMAIN 153..198 FT /note="CAP-Gly 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00045" FT DOMAIN 253..286 FT /note="CAP-Gly 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00045" FT DOMAIN 488..531 FT /note="CAP-Gly 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00045" FT DOMAIN 588..946 FT /note="USP" FT REGION 106..589 FT /note="Interaction with TRIP" FT /evidence="ECO:0000250|UniProtKB:Q9NQC7" FT REGION 311..350 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 386..409 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 390..465 FT /note="Interaction with TRAF2" FT /evidence="ECO:0000250|UniProtKB:Q9NQC7" FT REGION 466..680 FT /note="Interaction with IKBKG/NEMO" FT /evidence="ECO:0000250|UniProtKB:Q9NQC7" FT REGION 777..829 FT /note="B-box" FT /evidence="ECO:0000250|UniProtKB:Q9NQC7" FT COMPBIAS 325..350 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 597 FT /note="Nucleophile" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092, FT ECO:0000305|PubMed:32424362" FT ACT_SITE 867 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092" FT BINDING 784 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q9NQC7" FT BINDING 787 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q9NQC7" FT BINDING 795 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q9NQC7" FT BINDING 798 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q9NQC7" FT BINDING 813 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q9NQC7" FT BINDING 816 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q9NQC7" FT BINDING 821 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q9NQC7" FT BINDING 829 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q9NQC7" FT MOD_RES 383 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9NQC7" FT MOD_RES 414 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 418 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9NQC7" FT VAR_SEQ 304 FT /note="P -> PALS (in isoform 1)" FT /evidence="ECO:0000303|PubMed:16141072" FT /id="VSP_011278" FT VAR_SEQ 305..318 FT /note="DSVTQERRPPKLAF -> GTSKNILDQQLKGK (in isoform 3)" FT /evidence="ECO:0000303|PubMed:16141072" FT /id="VSP_011279" FT VAR_SEQ 319..952 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:16141072" FT /id="VSP_011280" FT MUTAGEN 597 FT /note="C->A: Loss of deubiquitinating activity." FT /evidence="ECO:0000269|PubMed:32424362" FT MUTAGEN 677 FT /note="D->G: Decreased inhibition of NF-kappa-B." FT /evidence="ECO:0000269|PubMed:32185393" FT MUTAGEN 715 FT /note="M->V: Increased inhibition of NF-kappa-B." FT /evidence="ECO:0000269|PubMed:32185393" FT CONFLICT 403 FT /note="M -> V (in Ref. 2; BAC30222)" FT /evidence="ECO:0000305" SQ SEQUENCE 952 AA; 106586 MW; 0AC0C7D4FF215A9C CRC64; MSSGLWSQEK VTSPYWEERI FYLLLQECSV TDKQTQKLLK VPKGSIGQYI QDRSVGHSRV PSTKGKKNQI GLKILEQPHA VLFVDEKDVV EINEKFTELL LAITNCEERL SLFRNRLRLS KGLQVDVGSP VKVQLRSGEE KFPGVVRFRG PLLAERTVSG IFFGVELLEE GRGQGFTDGV YQGKQLFQCD EDCGVFVALD KLELIEDDDN GLESDFAGPG DTMQVEPPPL EINSRVSLKV GESTESGTVI FCDVLPGKES LGYFVGVDMD NPIGNWDGRF DGVQLCSFAS VESTILLHIN DIIPDSVTQE RRPPKLAFMS RGVGDKGSSS HNKPKVTGST SDPGSRNRSE LFYTLNGSSV DSQQSKSKNP WYIDEVAEDP AKSLTEMSSD FGHSSPPPQP PSMNSLSSEN RFHSLPFSLT KMPNTNGSMA HSPLSLSVQS VMGELNSTPV QESPPLPISS GNAHGLEVGS LAEVKENPPF YGVIRWIGQP PGLSDVLAGL ELEDECAGCT DGTFRGTRYF TCALKKALFV KLKSCRPDSR FASLQPVSNQ IERCNSLAFG GYLSEVVEEN TPPKMEKEGL EIMIGKKKGI QGHYNSCYLD STLFCLFAFS SALDTVLLRP KEKNDIEYYS ETQELLRTEI VNPLRIYGYV CATKIMKLRK ILEKVEAASG FTSEEKDPEE FLNILFHDIL RVEPLLKIRS AGQKVQDCNF YQIFMEKNEK VGVPTIQQLL EWSFINSNLK FAEAPSCLII QMPRFGKDFK LFKKIFPSLE LNITDLLEDT PRQCRICGGL AMYECRECYD DPDISAGKIK QFCKTCSTQV HLHPRRLNHS YHPVSLPKDL PDWDWRHGCI PCQKMELFAV LCIETSHYVA FVKYGKDDSA WLFFDSMADR DGGQNGFNIP QVTPCPEVGE YLKMSLEDLH SLDSRRIQGC ARRLLCDAYM CMYQSPTMSL YK //