CYLD_PONAB
ID CYLD_PONAB Reviewed; 956 AA.
AC Q5RED8;
DT 18-MAR-2008, integrated into UniProtKB/Swiss-Prot.
DT 21-DEC-2004, sequence version 1.
DT 03-AUG-2022, entry version 98.
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 Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain cortex;
RG The German cDNA consortium;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
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; CR857591; CAH89869.1; -; mRNA.
DR RefSeq; NP_001124871.1; NM_001131399.1.
DR AlphaFoldDB; Q5RED8; -.
DR SMR; Q5RED8; -.
DR STRING; 9601.ENSPPYP00000008294; -.
DR MEROPS; C67.001; -.
DR GeneID; 100171734; -.
DR KEGG; pon:100171734; -.
DR CTD; 1540; -.
DR eggNOG; KOG3556; Eukaryota.
DR InParanoid; Q5RED8; -.
DR OrthoDB; 119442at2759; -.
DR Proteomes; UP000001595; 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:0005874; C:microtubule; IEA:UniProtKB-KW.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; 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:0061578; F:Lys63-specific deubiquitinase activity; ISS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; ISS:UniProtKB.
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: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:1902017; P:regulation of cilium assembly; ISS:UniProtKB.
DR GO; GO:0050727; P:regulation of inflammatory response; ISS:UniProtKB.
DR GO; GO:0010803; P:regulation of tumor necrosis factor-mediated signaling pathway; ISS:UniProtKB.
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 2: Evidence at transcript 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..956
FT /note="Ubiquitin carboxyl-terminal hydrolase CYLD"
FT /id="PRO_0000326148"
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 492..535
FT /note="CAP-Gly 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00045"
FT DOMAIN 592..950
FT /note="USP"
FT REGION 106..593
FT /note="Interaction with TRIP"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT REGION 309..353
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 392..411
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 394..469
FT /note="Interaction with TRAF2"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT REGION 470..684
FT /note="Interaction with IKBKG/NEMO"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT REGION 781..833
FT /note="B-box"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT COMPBIAS 328..353
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 601
FT /note="Nucleophile"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092"
FT ACT_SITE 871
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092"
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 791
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
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 802
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
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 820
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT BINDING 825
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT BINDING 833
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT MOD_RES 387
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT MOD_RES 418
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
FT MOD_RES 422
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9NQC7"
SQ SEQUENCE 956 AA; 107302 MW; ADDCE3C7241D828B CRC64;
MSSGLWSQDK VTSPYWEERV FYLLLQECSV TDKQTQKLLK VPKGSIGQYI QDRSVGHSRI
PSAKGKKNRI GLKILEQPHA VLFVDEKDVV EINEKFTELL LAITNCEERF SLFKNRNRLS
KGLQIDVGCP VKVQLRSGEE KFPGVVRFRG PLLAERTVSG IFFGVELLEE GRGQGFTDGV
YQGKQLFQCD EDCGVFVALD KLELIEDDDT ALESDYAGPG DTMQVELPPL EINSRVSLKV
GETIESGTVI FCDVLPGKES LGYFVGVDMD NPIGNWDGRF DGVQLCSFAC VESTILLHIN
DIIPALSESV TQERRPPKLA FMSRGVGDKG SSSHNKPKAT GSTSDPGNRN RSELFYTLNG
SSVDSQPQSK SKNTWYIDEV AEDPAKSLTE ISTDFDRSSP PLQPPPVNSL STENRFHSLP
FSLTKMPNTN GSIGHSPLSL SAQSVMEELN TAPVQESPPL AMPPGNSHGL EVGSLAEVKE
NPPFYGVIRW IGQPPGLNEV LAGLELEDEC AGCTDGTFRG TRYFTCALKK ALFVKLKSCR
PDSRFASLQP VSNQIERCNS LAFGGYLSEV VEENTPPKME KEGLEIMIGK KKGIQGHYNS
CYLDSTLFCL FAFSSVLDTV LLRPKEKNDV EYYSETQELL RTEIVNPLRI YGYVCATKIM
KLRKILEKVE AASGFTSEEK DPEEFLNILF HHILRVEPLL KIRSAGQKVQ DCYFYQIFME
KNEKVGVPTI QQLLEWSFIN SNLKFAEAPS CLIIQMPRFG KDFKLFKKIF PSLELNITDL
LEDTPRQCRI CGGLAMYECR ECYDDPDISA GKIKQFCKTC NTQVHLHPKR LNHKYNPVSL
PKDLPDWDWR HGCIPCQNME LFAVLCIETS HYVAFVKYGK DDSAWLFFDS MADRDGGQNG
FNIPQVTPCP EVGEYLKMSL EDLHSLDSRR IQGCARRLLC DAYMCMYQSP TMSLYK
