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Q80TQ2 (CYLD_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 103. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Ubiquitin carboxyl-terminal hydrolase CYLD

EC=3.4.19.12
Alternative name(s):
Deubiquitinating enzyme CYLD
Ubiquitin thioesterase CYLD
Ubiquitin-specific-processing protease CYLD
Gene names
Name:Cyld
Synonyms:Cyld1, Kiaa0849
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length952 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Protease that specifically cleaves 'Lys-63'-linked polyubiquitin chains. Has endodeubiquitinase activity. Plays an important role in the regulation of pathways leading to NF-kappa-B activation. Contributes to the regulation of cell survival, proliferation and differentiation via its effects on NF-kappa-B activation. Negative regulator of Wnt signaling. Inhibits HDAC6 and thereby promotes acetylation of alpha-tubulin and stabilization of microtubules. Plays a role in the regulation of microtubule dynamics, and thereby contributes to the regulation of cell proliferation, cell polarization, cell migration, and angiogenesis. Required for normal cell cycle progress and normal cytokinesis. Inhibits nuclear translocation of NF-kappa-B By similarity. Plays a role in the regulation of inflammation and the innate immune response, via its effects on NF-kappa-B activation. Dispensable for the maturation of intrathymic natural killer cells, but required for the continued survival of immature natural killer cells. Negatively regulates TNFRSF11A signaling and osteoclastogenesis. Ref.4 Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10

Catalytic activity

Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).

Subunit structure

Interacts (via CAP-Gly domain) with IKBKG/NEMO (via proline-rich C-terminal region). Interacts with TRAF2 and TRIP. Interacts with PLK1, DVL1, DVL3, MAVS, TBK1, IKKE and DDX58 By similarity. Interacts (via CAP-Gly domain) with microtubules. Interacts with HDAC6 and BCL3. Interacts with SQSTM1 and MAP3K7. Identified in a complex with TRAF6 and SQSTM1. Ref.4 Ref.6 Ref.8 Ref.10

Subcellular location

Cytoplasm. Cytoplasmperinuclear region. Cytoplasmcytoskeleton. Cell membrane; Peripheral membrane protein; Cytoplasmic side By similarity. Note: Detected at the microtubule cytoskeleton during interphase. Detected at the midbody during telophase. Ref.4 Ref.10

Induction

Up-regulated by TNFRSF11A. Ref.8

Post-translational modification

Phosphorylated on several serine residues by IKKA and/or IKKB in response to immune stimuli. Phosphorylation requires IKBKG. Phosphorylation abolishes TRAF2 deubiquitination, interferes with the activation of Jun kinases, and strongly reduces CD40-dependent gene activation by NF-kappa-B By similarity.

Disruption phenotype

No obvious phenotype, but mice are highly susceptible to carcinogens and are prone to chemically induced skin tumors. The number of natural killer T-cells is much reduced. Animals are highly susceptible to bacteria-induced pneumonia, due to an over active innate immune response. Animals spontaneously develop colonic inflammation, due to constitutive expression of several proinflammatory genes in the colon. Animals exhibit abnormal osteoclast differentiation, leading to osteoporosis. Ref.4 Ref.5 Ref.6 Ref.7 Ref.8

Sequence similarities

Belongs to the peptidase C19 family.

Contains 3 CAP-Gly domains.

Contains 1 USP domain.

Sequence caution

The sequence BAC65671.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
   Biological processUbl conjugation pathway
Wnt signaling pathway
   Cellular componentCell membrane
Cytoplasm
Cytoskeleton
Membrane
Microtubule
   Coding sequence diversityAlternative splicing
   DomainRepeat
   LigandMetal-binding
Zinc
   Molecular functionHydrolase
Protease
Thiol protease
   PTMPhosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processWnt signaling pathway

Inferred from electronic annotation. Source: UniProtKB-KW

innate immune response

Inferred from Biological aspect of Ancestor. Source: RefGenome

necroptotic process

Inferred from genetic interaction PubMed 21052097PubMed 22037414. Source: MGI

negative regulation of NF-kappaB import into nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of NF-kappaB transcription factor activity

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of canonical Wnt signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of extrinsic apoptotic signaling pathway

Inferred from Biological aspect of Ancestor. Source: RefGenome

protein K63-linked deubiquitination

Inferred from sequence or structural similarity. Source: UniProtKB

protein deubiquitination

Inferred from mutant phenotype PubMed 22037414. Source: MGI

regulation of intrinsic apoptotic signaling pathway

Inferred from electronic annotation. Source: Ensembl

regulation of microtubule cytoskeleton organization

Inferred from electronic annotation. Source: Ensembl

regulation of mitotic cell cycle

Inferred from Biological aspect of Ancestor. Source: RefGenome

ripoptosome assembly involved in necroptotic process

Inferred from mutant phenotype PubMed 22037414. Source: MGI

ubiquitin-dependent protein catabolic process

Inferred from electronic annotation. Source: InterPro

   Cellular_componentcytoplasmic microtubule

Inferred from electronic annotation. Source: Ensembl

cytosol

Inferred from sequence or structural similarity. Source: UniProtKB

extrinsic component of cytoplasmic side of plasma membrane

Inferred from electronic annotation. Source: Ensembl

midbody

Inferred from electronic annotation. Source: Ensembl

perinuclear region of cytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionubiquitin-specific protease activity

Inferred from sequence or structural similarity. Source: UniProtKB

zinc ion binding

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 2 (identifier: Q80TQ2-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 1 (identifier: Q80TQ2-2)

The sequence of this isoform differs from the canonical sequence as follows:
     304-304: P → PALS
Isoform 3 (identifier: Q80TQ2-3)

The sequence of this isoform differs from the canonical sequence as follows:
     305-318: DSVTQERRPPKLAF → GTSKNILDQQLKGK
     319-952: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 952952Ubiquitin carboxyl-terminal hydrolase CYLD
PRO_0000080699

Regions

Domain153 – 19846CAP-Gly 1
Domain253 – 28634CAP-Gly 2
Domain488 – 53144CAP-Gly 3
Domain588 – 946359USP
Region106 – 589484Interaction with TRIP By similarity
Region390 – 46576Interaction with TRAF2 By similarity
Region466 – 680215Interaction with IKBKG/NEMO By similarity

Sites

Active site5971Nucleophile By similarity
Active site8671Proton acceptor By similarity
Metal binding7841Zinc 1 By similarity
Metal binding7871Zinc 1 By similarity
Metal binding7951Zinc 2 By similarity
Metal binding7981Zinc 2 By similarity
Metal binding8131Zinc 1 By similarity
Metal binding8161Zinc 1 By similarity
Metal binding8211Zinc 2 By similarity
Metal binding8291Zinc 2 By similarity

Amino acid modifications

Modified residue4141Phosphoserine By similarity

Natural variations

Alternative sequence3041P → PALS in isoform 1.
VSP_011278
Alternative sequence305 – 31814DSVTQ…PKLAF → GTSKNILDQQLKGK in isoform 3.
VSP_011279
Alternative sequence319 – 952634Missing in isoform 3.
VSP_011280

Experimental info

Sequence conflict4031M → V in BAC30222. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Isoform 2 [UniParc].

Last modified August 16, 2004. Version 2.
Checksum: 0AC0C7D4FF215A9C

FASTA952106,586
        10         20         30         40         50         60 
MSSGLWSQEK VTSPYWEERI FYLLLQECSV TDKQTQKLLK VPKGSIGQYI QDRSVGHSRV 

        70         80         90        100        110        120 
PSTKGKKNQI GLKILEQPHA VLFVDEKDVV EINEKFTELL LAITNCEERL SLFRNRLRLS 

       130        140        150        160        170        180 
KGLQVDVGSP VKVQLRSGEE KFPGVVRFRG PLLAERTVSG IFFGVELLEE GRGQGFTDGV 

       190        200        210        220        230        240 
YQGKQLFQCD EDCGVFVALD KLELIEDDDN GLESDFAGPG DTMQVEPPPL EINSRVSLKV 

       250        260        270        280        290        300 
GESTESGTVI FCDVLPGKES LGYFVGVDMD NPIGNWDGRF DGVQLCSFAS VESTILLHIN 

       310        320        330        340        350        360 
DIIPDSVTQE RRPPKLAFMS RGVGDKGSSS HNKPKVTGST SDPGSRNRSE LFYTLNGSSV 

       370        380        390        400        410        420 
DSQQSKSKNP WYIDEVAEDP AKSLTEMSSD FGHSSPPPQP PSMNSLSSEN RFHSLPFSLT 

       430        440        450        460        470        480 
KMPNTNGSMA HSPLSLSVQS VMGELNSTPV QESPPLPISS GNAHGLEVGS LAEVKENPPF 

       490        500        510        520        530        540 
YGVIRWIGQP PGLSDVLAGL ELEDECAGCT DGTFRGTRYF TCALKKALFV KLKSCRPDSR 

       550        560        570        580        590        600 
FASLQPVSNQ IERCNSLAFG GYLSEVVEEN TPPKMEKEGL EIMIGKKKGI QGHYNSCYLD 

       610        620        630        640        650        660 
STLFCLFAFS SALDTVLLRP KEKNDIEYYS ETQELLRTEI VNPLRIYGYV CATKIMKLRK 

       670        680        690        700        710        720 
ILEKVEAASG FTSEEKDPEE FLNILFHDIL RVEPLLKIRS AGQKVQDCNF YQIFMEKNEK 

       730        740        750        760        770        780 
VGVPTIQQLL EWSFINSNLK FAEAPSCLII QMPRFGKDFK LFKKIFPSLE LNITDLLEDT 

       790        800        810        820        830        840 
PRQCRICGGL AMYECRECYD DPDISAGKIK QFCKTCSTQV HLHPRRLNHS YHPVSLPKDL 

       850        860        870        880        890        900 
PDWDWRHGCI PCQKMELFAV LCIETSHYVA FVKYGKDDSA WLFFDSMADR DGGQNGFNIP 

       910        920        930        940        950 
QVTPCPEVGE YLKMSLEDLH SLDSRRIQGC ARRLLCDAYM CMYQSPTMSL YK 

« Hide

Isoform 1 [UniParc].

Checksum: E8D55AE26D90241F
Show »

FASTA955106,857
Isoform 3 [UniParc].

Checksum: 23465D36304356BF
Show »

FASTA31835,288

References

« Hide 'large scale' references
[1]"Prediction of the coding sequences of mouse homologues of KIAA gene: II. The complete nucleotide sequences of 400 mouse KIAA-homologous cDNAs identified by screening of terminal sequences of cDNA clones randomly sampled from size-fractionated libraries."
Okazaki N., Kikuno R., Ohara R., Inamoto S., Aizawa H., Yuasa S., Nakajima D., Nagase T., Ohara O., Koga H.
DNA Res. 10:35-48(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
Tissue: Brain.
[2]"The transcriptional landscape of the mammalian genome."
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-620 (ISOFORM 1).
Strain: C57BL/6J.
Tissue: Cerebellum and Hypothalamus.
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
Strain: FVB/N.
Tissue: Mammary gland.
[4]"Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling."
Massoumi R., Chmielarska K., Hennecke K., Pfeifer A., Fassler R.
Cell 125:665-677(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE, INTERACTION WITH BCL3, SUBCELLULAR LOCATION.
[5]"Regulation of T cell development by the deubiquitinating enzyme CYLD."
Reiley W.W., Zhang M., Jin W., Losiewicz M., Donohue K.B., Norbury C.C., Sun S.C.
Nat. Immunol. 7:411-417(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[6]"Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses."
Reiley W.W., Jin W., Lee A.J., Wright A., Wu X., Tewalt E.F., Leonard T.O., Norbury C.C., Fitzpatrick L., Zhang M., Sun S.C.
J. Exp. Med. 204:1475-1485(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH MAP3K7, DISRUPTION PHENOTYPE.
[7]"CYLD is a crucial negative regulator of innate immune response in Escherichia coli pneumonia."
Lim J.H., Ha U.H., Woo C.H., Xu H., Li J.D.
Cell. Microbiol. 10:2247-2256(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[8]"Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice."
Jin W., Chang M., Paul E.M., Babu G., Lee A.J., Reiley W., Wright A., Zhang M., You J., Sun S.C.
J. Clin. Invest. 118:1858-1866(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE, FUNCTION, INTERACTION WITH SQSTM1, IDENTIFICATION IN A COMPLEX WITH TRAF6 AND SQSTM1, INDUCTION.
[9]"CYLD regulates angiogenesis by mediating vascular endothelial cell migration."
Gao J., Sun L., Huo L., Liu M., Li D., Zhou J.
Blood 115:4130-4137(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[10]"CYLD negatively regulates cell-cycle progression by inactivating HDAC6 and increasing the levels of acetylated tubulin."
Wickstrom S.A., Masoumi K.C., Khochbin S., Fassler R., Massoumi R.
EMBO J. 29:131-144(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH HDAC6, BCL3 AND MICROTUBULES, SUBCELLULAR LOCATION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AK122389 mRNA. Translation: BAC65671.1. Different initiation.
AK039054 mRNA. Translation: BAC30222.1.
AK042764 mRNA. Translation: BAC31357.1.
BC042438 mRNA. Translation: AAH42438.1.
BC049879 mRNA. Translation: AAH49879.1.
RefSeqNP_001121642.1. NM_001128170.2.
NP_001121643.1. NM_001128171.2.
NP_775545.1. NM_173369.3.
XP_006531477.1. XM_006531414.1.
XP_006531478.1. XM_006531415.1.
XP_006531479.1. XM_006531416.1.
XP_006531480.1. XM_006531417.1.
XP_006531481.1. XM_006531418.1.
UniGeneMm.490395.

3D structure databases

ProteinModelPortalQ80TQ2.
SMRQ80TQ2. Positions 125-206, 228-306, 453-546, 579-952.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid216612. 12 interactions.
IntActQ80TQ2. 4 interactions.
MINTMINT-7561827.

Protein family/group databases

MEROPSC67.001.

PTM databases

PhosphoSiteQ80TQ2.

Proteomic databases

PaxDbQ80TQ2.
PRIDEQ80TQ2.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000098519; ENSMUSP00000096119; ENSMUSG00000036712. [Q80TQ2-2]
ENSMUST00000109626; ENSMUSP00000105254; ENSMUSG00000036712. [Q80TQ2-1]
GeneID74256.
KEGGmmu:74256.
UCSCuc009mrt.2. mouse. [Q80TQ2-1]
uc009mrw.2. mouse. [Q80TQ2-2]

Organism-specific databases

CTD1540.
MGIMGI:1921506. Cyld.
RougeSearch...

Phylogenomic databases

eggNOGNOG313578.
GeneTreeENSGT00390000018123.
HOGENOMHOG000006796.
HOVERGENHBG051281.
KOK08601.
OrthoDBEOG72ZCDM.
PhylomeDBQ80TQ2.

Gene expression databases

ArrayExpressQ80TQ2.
BgeeQ80TQ2.
CleanExMM_CYLD.
GenevestigatorQ80TQ2.

Family and domain databases

Gene3D2.30.30.190. 3 hits.
InterProIPR000938. CAP-Gly_domain.
IPR018200. Pept_C19ubi-hydrolase_C_CS.
IPR001394. Peptidase_C19_UCH.
IPR028889. UCH/PAN2.
[Graphical view]
PfamPF01302. CAP_GLY. 3 hits.
PF00443. UCH. 1 hit.
[Graphical view]
SMARTSM01052. CAP_GLY. 3 hits.
[Graphical view]
SUPFAMSSF74924. SSF74924. 3 hits.
PROSITEPS00845. CAP_GLY_1. 1 hit.
PS50245. CAP_GLY_2. 2 hits.
PS00972. USP_1. 1 hit.
PS50235. USP_3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio340262.
SOURCESearch...

Entry information

Entry nameCYLD_MOUSE
AccessionPrimary (citable) accession number: Q80TQ2
Secondary accession number(s): Q80VB3 expand/collapse secondary AC list , Q8BXZ3, Q8BYL9, Q8CGB0
Entry history
Integrated into UniProtKB/Swiss-Prot: August 16, 2004
Last sequence update: August 16, 2004
Last modified: April 16, 2014
This is version 103 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Peptidase families

Classification of peptidase families and list of entries

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot