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   24-JAN-2024, entry version 103.
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). Removes also 'Lys-63'-linked
CC       polyubiquitin chains of MAP3K1 and MA3P3K3, which inhibit their
CC       interaction with MAP2K1 and MAP2K2 (By similarity).
CC       {ECO:0000250|UniProtKB:Q80TQ2, 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 RIGI. 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; 5397179at2759; -.
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:K63-linked 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 non-canonical NF-kappaB signal transduction; 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:1990108; P:protein linear deubiquitination; ISS:UniProtKB.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
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: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.
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
//