CYLD_RAT
ID CYLD_RAT Reviewed; 953 AA.
AC Q66H62;
DT 18-MAR-2008, integrated into UniProtKB/Swiss-Prot.
DT 11-OCT-2004, sequence version 1.
DT 03-AUG-2022, entry version 127.
DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase CYLD;
DE EC=3.4.19.12 {ECO:0000250|UniProtKB:Q9NQC7};
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;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
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 [2]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-415 AND SER-419, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
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. Negatively regulates NF-
CC kappa-B activation by deubiquitinating upstream signaling factors.
CC Contributes to the regulation of cell survival, proliferation and
CC differentiation via its effects on NF-kappa-B activation. Negative
CC regulator of Wnt signaling. Inhibits HDAC6 and thereby promotes
CC acetylation of alpha-tubulin and stabilization of microtubules. 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. Required for normal cell cycle progress
CC and normal cytokinesis. Inhibits nuclear translocation of NF-kappa-B.
CC Plays a role in the regulation of inflammation and the innate immune
CC response, via its effects on NF-kappa-B activation (By similarity).
CC Dispensable for the maturation of intrathymic natural killer cells, but
CC required for the continued survival of immature natural killer cells.
CC Negatively regulates TNFRSF11A signaling and osteoclastogenesis.
CC Involved in the regulation of ciliogenesis, allowing ciliary basal
CC bodies to migrate and dock to the plasma membrane; this process does
CC not depend on NF-kappa-B activation (By similarity). Ability to remove
CC linear ('Met-1'-linked) polyubiquitin chains regulates innate immunity
CC and TNF-alpha-induced necroptosis: recruited to the LUBAC complex via
CC interaction with SPATA2 and restricts linear polyubiquitin formation on
CC target proteins. 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 (By similarity). 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 (By
CC similarity). Removes 'Lys-63' linked polyubiquitin chain of MAP3K7,
CC which inhibits phosphorylation and blocks downstream activation of the
CC JNK-p38 kinase cascades (By similarity). {ECO:0000250|UniProtKB:Q80TQ2,
CC ECO:0000250|UniProtKB:Q9NQC7}.
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:0000250|UniProtKB:Q9NQC7};
CC -!- SUBUNIT: Interacts (via CAP-Gly domain) with IKBKG/NEMO (via proline-
CC rich C-terminal region). Interacts with TRAF2 and TRIP. Interacts with
CC PLK1, DVL1, DVL3, MAVS, TBK1, IKKE and DDX58. Interacts (via CAP-Gly
CC domain) with microtubules. Interacts with HDAC6 and BCL3 (By
CC similarity). Interacts with MAP3K7. Identified in a complex with TRAF6
CC and SQSTM1 (By similarity). Interacts with OPTN and SQSTM1 (By
CC similarity). Interacts with CEP350. Interacts with RNF31; the
CC interaction is indirect and is mediated via SPATA2. Interacts with
CC SPATA2 (via the PUB domain); the interaction is direct and recruits
CC CYLD to the LUBAC complex, thereby regulating TNF-alpha-induced
CC necroptosis (By similarity). {ECO:0000250|UniProtKB:Q80TQ2,
CC ECO:0000250|UniProtKB:Q9NQC7}.
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:0000250|UniProtKB:Q80TQ2}. 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:Q80TQ2,
CC ECO:0000250|UniProtKB:Q9NQC7}.
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:0000250|UniProtKB:Q80TQ2,
CC ECO:0000250|UniProtKB:Q9NQC7}.
CC -!- SIMILARITY: Belongs to the peptidase C19 family. {ECO:0000305}.
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DR EMBL; BC082001; AAH82001.1; -; mRNA.
DR RefSeq; NP_001017380.1; NM_001017380.1.
DR AlphaFoldDB; Q66H62; -.
DR SMR; Q66H62; -.
DR BioGRID; 260280; 3.
DR STRING; 10116.ENSRNOP00000018888; -.
DR MEROPS; C67.001; -.
DR iPTMnet; Q66H62; -.
DR PhosphoSitePlus; Q66H62; -.
DR PaxDb; Q66H62; -.
DR PRIDE; Q66H62; -.
DR GeneID; 312937; -.
DR KEGG; rno:312937; -.
DR CTD; 1540; -.
DR RGD; 1308346; Cyld.
DR eggNOG; KOG3556; Eukaryota.
DR InParanoid; Q66H62; -.
DR OrthoDB; 119442at2759; -.
DR PhylomeDB; Q66H62; -.
DR Reactome; R-RNO-168638; NOD1/2 Signaling Pathway.
DR Reactome; R-RNO-5357786; TNFR1-induced proapoptotic signaling.
DR Reactome; R-RNO-5357905; Regulation of TNFR1 signaling.
DR Reactome; R-RNO-5357956; TNFR1-induced NFkappaB signaling pathway.
DR Reactome; R-RNO-5689880; Ub-specific processing proteases.
DR PRO; PR:Q66H62; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005813; C:centrosome; ISS:UniProtKB.
DR GO; GO:0036064; C:ciliary basal body; ISS:UniProtKB.
DR GO; GO:0097542; C:ciliary tip; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0031234; C:extrinsic component of cytoplasmic side of plasma membrane; ISO:RGD.
DR GO; GO:0005874; C:microtubule; IEA:UniProtKB-KW.
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; ISS:UniProtKB.
DR GO; GO:1990380; F:Lys48-specific deubiquitinase activity; ISO:RGD.
DR GO; GO:0061578; F:Lys63-specific deubiquitinase activity; ISS:UniProtKB.
DR GO; GO:0070064; F:proline-rich region binding; ISO:RGD.
DR GO; GO:0019901; F:protein kinase binding; ISO:RGD.
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; ISO:RGD.
DR GO; GO:0048872; P:homeostasis of number of cells; ISO:RGD.
DR GO; GO:0045087; P:innate immune response; ISS:UniProtKB.
DR GO; GO:0070266; P:necroptotic process; ISO:RGD.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; ISS:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; ISS:UniProtKB.
DR GO; GO:2000493; P:negative regulation of interleukin-18-mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:0046329; P:negative regulation of JNK cascade; ISS:UniProtKB.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
DR GO; GO:1901223; P:negative regulation of NIK/NF-kappaB signaling; ISS:UniProtKB.
DR GO; GO:1903753; P:negative regulation of p38MAPK cascade; ISS:UniProtKB.
DR GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; ISO:RGD.
DR GO; GO:1903829; P:positive regulation of protein localization; ISO:RGD.
DR GO; GO:0045582; P:positive regulation of T cell differentiation; ISO:RGD.
DR GO; GO:0050862; P:positive regulation of T cell receptor signaling pathway; ISO:RGD.
DR GO; GO:0016579; P:protein deubiquitination; ISS:UniProtKB.
DR GO; GO:0070536; P:protein K63-linked deubiquitination; ISS:UniProtKB.
DR GO; GO:1990108; P:protein linear deubiquitination; ISS:UniProtKB.
DR GO; GO:0045577; P:regulation of B cell differentiation; ISO:RGD.
DR GO; GO:1902017; P:regulation of cilium assembly; ISS:UniProtKB.
DR GO; GO:0050727; P:regulation of inflammatory response; ISS:UniProtKB.
DR GO; GO:2001242; P:regulation of intrinsic apoptotic signaling pathway; ISO:RGD.
DR GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; ISO:RGD.
DR GO; GO:0007346; P:regulation of mitotic cell cycle; ISO:RGD.
DR GO; GO:0060544; P:regulation of necroptotic process; ISO:RGD.
DR GO; GO:0043393; P:regulation of protein binding; ISO:RGD.
DR GO; GO:0010803; P:regulation of tumor necrosis factor-mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:1901026; P:ripoptosome assembly involved in necroptotic process; ISO:RGD.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:InterPro.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR Gene3D; 2.30.30.190; -; 3.
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 Pfam; PF01302; CAP_GLY; 2.
DR Pfam; PF00443; UCH; 1.
DR SMART; SM01052; CAP_GLY; 3.
DR SUPFAM; SSF54001; SSF54001; 1.
DR SUPFAM; SSF74924; SSF74924; 3.
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.
PE 1: Evidence at protein level;
KW Cell membrane; Cell projection; Cytoplasm; Cytoskeleton; Hydrolase;
KW Immunity; Innate immunity; Membrane; Metal-binding; Microtubule;
KW Phosphoprotein; Protease; Reference proteome; Repeat; Thiol protease;
KW Ubl conjugation; Ubl conjugation pathway; Wnt signaling pathway; Zinc.
FT CHAIN 1..953
FT /note="Ubiquitin carboxyl-terminal hydrolase CYLD"
FT /id="PRO_0000326149"
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 489..532
FT /note="CAP-Gly 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00045"
FT DOMAIN 589..947
FT /note="USP"
FT REGION 106..590
FT /note="Interaction with TRIP"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT REGION 318..350
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 387..410
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 391..466
FT /note="Interaction with TRAF2"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT REGION 467..681
FT /note="Interaction with IKBKG/NEMO"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT REGION 778..830
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 598
FT /note="Nucleophile"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092"
FT ACT_SITE 868
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092"
FT BINDING 785
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT BINDING 788
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT BINDING 796
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT BINDING 799
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT BINDING 814
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT BINDING 817
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT BINDING 822
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT BINDING 830
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT MOD_RES 384
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT MOD_RES 415
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 419
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
SQ SEQUENCE 953 AA; 106713 MW; 573B59E9BD795252 CRC64;
MSSGLWNQEK VTSPYWEERL FYLLLQECSV TDKQTQKLLR VPKGSIGQYI QDRSVGHSRV
PSAKGKKNQI GLKILEQPHA VLFVDEKDVV EINEKFTELL LAITNCEERL SLFRNRIRLS
KGLQVDVGSP VRVQLRSGEE KFPGVVRFRG PLLAERTVSG IFFGVELLEE GRGQGFTDGV
YQGKQLFQCD EDCGVFVALD KLELIEDDDN GLESDFAGPG DTVQVEPPPL EINSRVSLKV
GESTESGTVI FCDVLPGKES LGYFVGVDMD NPIGNWDGRF DGVQLCSFAS VESTVLLHIN
DIIPDSVTQE RRPPKLAFMS RGVGDKGSSS HNKPKVTGST SDPGSRNRSE LFYTLNGSSV
DSQQQSKSKN PWYIDEVAED PAKSLTEMSS DFGHSSPPPQ PPSMNSLSSE NRFHSLPFSL
TKMPNTNGSM AHSPLSLSVQ SVMGELNSTP VQESPPMPSS SGNAHGLEVG SLAEVKENPP
FYGVIRWIGQ PPGLSDVLAG LELEDECAGC TDGTFRGTRY FTCALKKALF VKLKSCRPDS
RFASLQPVSN QIERCNSLAF GGYLSEVVEE NTPPKMEKEG LEIMIGKKKG IQGHYNSCYL
DSTLFCLFAF SSALDTVLLR PKEKNDVEYY SETQELLRTE IVNPLRIYGY VCATKIMKLR
KILEKVEAAS GFTSEEKDPE EFLNILFHDI LRVEPLLKIR SAGQKVQDCN FYQIFMEKNE
KVGVPTIQQL LEWSFINSNL KFAEAPSCLI IQMPRFGKDF KLFKKIFPSL ELNITDLLED
TPRQCRICGG LAMYECRECY DDPDISAGKI KQFCKTCSTQ VHLHPRRLNH TYHPVSLPKD
LPDWDWRHGC IPCQKMELFA VLCIETSHYV AFVKYGKDDS AWLFFDSMAD RDGGQNGFNI
PQVTPCPEVG EYLKMSLEDL HSLDSRRIQG CARRLLCDAY MCMYQSPTMS LYK
