Q9NQC7 (CYLD_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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
ORF Names:	HSPC057

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	956 AA.
Sequence status	Complete.
Protein existence	Evidence 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. 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 By similarity. Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.15 Ref.16 Ref.17 Ref.22
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). Ref.22
Enzyme regulation	Inhibited by phosphorylation at serine residues. Ref.10
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. 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 By similarity. Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.16 Ref.17 Ref.18
Subcellular location	Cytoplasm. Cytoplasm › perinuclear region. Cytoplasm › cytoskeleton. Cell membrane; Peripheral membrane protein; Cytoplasmic side. Note: Detected at the microtubule cytoskeleton during interphase. Detected at the midbody during telophase. Ref.9 Ref.11 Ref.13 Ref.15 Ref.16 Ref.22
Tissue specificity	Detected in fetal brain, testis, and skeletal muscle, and at a lower level in adult brain, leukocytes, liver, heart, kidney, spleen, ovary and lung. Isoform 2 is found in all tissues except kidney. Ref.1
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. Ref.10
Involvement in disease	Familial cylindromatosis (FCYL) [MIM:132700]: Autosomal dominant and highly tumor type-specific disorder. The tumors (known as cylindromas because of their characteristic microscopic architecture) are believed to arise from or recapitulate the appearance of the eccrine or apocrine cells of the skin that secrete sweat and scent respectively. Cylindromas arise predominantly in hairy parts of the body with approximately 90% on the head and neck. The development of a confluent mass which may ulcerate or become infected has led to the designation 'turban tumor syndrome'. The skin tumors show differentiation in the direction of hair structures, hence the synonym trichoepithelioma. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.20 Ref.26 Multiple familial trichoepithelioma 1 (MFT1) [MIM:601606]: Autosomal dominant dermatosis characterized by the presence of many skin tumors predominantly on the face. Since histologic examination shows dermal aggregates of basaloid cells with connection to or differentiation toward hair follicles, this disorder has been thought to represent a benign hamartoma of the pilosebaceous apparatus. Trichoepitheliomas can degenerate into basal cell carcinoma. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.23 Ref.24 Ref.26 Brooke-Spiegler syndrome (BRSS) [MIM:605041]: An autosomal dominant disorder characterized by the appearance of multiple skin appendage tumors such as cylindroma, trichoepithelioma, and spiradenoma. These tumors are typically located in the head and neck region, appear in early adulthood, and gradually increase in size and number throughout life. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.20 Ref.21 Ref.23 Ref.25
Sequence similarities	Belongs to the peptidase C67 family. Contains 3 CAP-Gly domains.
Sequence caution	The sequence AAF29029.1 differs from that shown. Reason: Frameshift at positions 776, 808 and 932. The sequence BAA74872.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
Biological process	Cell cycle Ubl conjugation pathway Wnt signaling pathway
Cellular component	Cell membrane Cytoplasm Cytoskeleton Membrane Microtubule
Coding sequence diversity	Alternative splicing
Disease	Disease mutation Tumor suppressor
Domain	Repeat
Ligand	Metal-binding Zinc
Molecular function	Hydrolase Protease Thiol protease
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	Wnt receptor signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW cell cycle Inferred from electronic annotation. Source: UniProtKB-KW induction of apoptosis Inferred from direct assay PubMed 21525013. Source: UniProtKB innate immune response Traceable author statement. Source: Reactome negative regulation of NF-kappaB import into nucleus Inferred from direct assay Ref.22. Source: UniProtKB negative regulation of NF-kappaB transcription factor activity Inferred from direct assay Ref.22. Source: UniProtKB negative regulation of canonical Wnt receptor signaling pathway Inferred from mutant phenotype Ref.17. Source: UniProtKB negative regulation of type I interferon production Traceable author statement. Source: Reactome nucleotide-binding oligomerization domain containing signaling pathway Traceable author statement. Source: Reactome positive regulation of extrinsic apoptotic signaling pathway Inferred from mutant phenotype PubMed 21525013. Source: UniProtKB protein K63-linked deubiquitination Inferred from direct assay Ref.22Ref.12. Source: UniProtKB regulation of microtubule cytoskeleton organization Inferred from mutant phenotype Ref.15. Source: UniProtKB regulation of mitotic cell cycle Inferred from mutant phenotype Ref.11. Source: UniProtKB ubiquitin-dependent protein catabolic process Inferred from electronic annotation. Source: InterPro
Cellular_component	cytosol Inferred from direct assay Ref.22. Source: UniProtKB extrinsic to internal side of plasma membrane Inferred from direct assay Ref.15. Source: UniProtKB microtubule Inferred from electronic annotation. Source: UniProtKB-KW perinuclear region of cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ubiquitin thiolesterase activity Inferred from electronic annotation. Source: InterPro ubiquitin-specific protease activity Inferred from direct assay Ref.22Ref.12. Source: UniProtKB zinc ion binding Inferred from direct assay Ref.22. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9NQC7-1)

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 2 (identifier: Q9NQC7-2)

The sequence of this isoform differs from the canonical sequence as follows:
     305-307: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 956

956

Ubiquitin carboxyl-terminal hydrolase CYLD

PRO_0000080698

Regions

Domain

153 – 198

46

CAP-Gly 1

Domain

253 – 286

34

CAP-Gly 2

Domain

492 – 535

44

CAP-Gly 3

Region

106 – 593

488

Interaction with TRIP

Region

394 – 469

76

Interaction with TRAF2

Region

470 – 554

85

Interaction with IKBKG/NEMO

Sites

Active site

601

1

Nucleophile Ref.22

Active site

871

1

Proton acceptor Probable

Metal binding

788

1

Zinc 1

Metal binding

791

1

Zinc 1

Metal binding

799

1

Zinc 2

Metal binding

802

1

Zinc 2

Metal binding

817

1

Zinc 1

Metal binding

820

1

Zinc 1

Metal binding

825

1

Zinc 2

Metal binding

833

1

Zinc 2

Amino acid modifications

Modified residue

418

1

Phosphoserine Ref.10

Natural variations

Alternative sequence

305 – 307

3

Missing in isoform 2.

VSP_011277

Natural variant

747

1

E → G in MFT1 and BRSS. Ref.23

VAR_045967

Experimental info

Mutagenesis

418

1

S → A: Reduced phosphorylation; when associated with A-422; A-432 and A-436. Loss of phosphorylation; when associated with A-422; A-432; A-436; A-439; A-441 and A-444. Ref.10

Mutagenesis

418

1

S → E: Abolishes deubiquitination of TRAF2; when associated with E-422; E-432; E-436; E-439; E-441 and E-444. Ref.10

Mutagenesis

422

1

S → A: Reduced phosphorylation; when associated with A-418; A-432 and A-436. Loss of phosphorylation; when associated with A-418; A-432; A-436; A-439; A-441 and A-444. Ref.10

Mutagenesis

422

1

S → E: Abolishes deubiquitination of TRAF2; when associated with E-418; E-432; E-436; E-439; E-441 and E-444. Ref.10

Mutagenesis

432

1

S → A: Slightly reduced phosphorylation; when associated with A-436. Reduced phosphorylation; when associated with A-418; A-422 and A-436. Loss of phosphorylation; when associated with A-418; A-422; A-436; A-439; A-441 and A-444. Ref.10

Mutagenesis

432

1

S → E: Abolishes deubiquitination of TRAF2; when associated with E-418; E-422; E-436; E-439; E-441 and E-444. Ref.10

Mutagenesis

436

1

S → A: Slightly reduced phosphorylation; when associated with A-432. Reduced phosphorylation; when associated with A-418; A-422 and A-432. Loss of phosphorylation; when associated with A-418; A-422; A-432; A-439; A-441 and A-444. Ref.10

Mutagenesis

436

1

S → E: Abolishes deubiquitination of TRAF2; when associated with E-418; E-422; E-432; E-439; E-441 and E-444. Ref.10

Mutagenesis

439

1

S → A: Loss of phosphorylation; when associated with A-418; A-422; A-432; A-436; A-441 and A-444. Ref.10

Mutagenesis

439

1

S → E: Abolishes deubiquitination of TRAF2; when associated with E-418; E-422; E-432; E-436; E-441 and E-444. Ref.10

Mutagenesis

441

1

S → A: Loss of phosphorylation; when associated with A-418; A-422; A-432; A-436; A-439 and A-444. Ref.10

Mutagenesis

441

1

S → E: Abolishes deubiquitination of TRAF2; when associated with E-418; E-422; E-432; E-436; E-439 and E-444. Ref.10

Mutagenesis

444

1

S → A: Loss of phosphorylation; when associated with A-418; A-422; A-432; A-436; A-439 and A-441. Ref.10

Mutagenesis

444

1

S → E: Abolishes deubiquitination of TRAF2; when associated with E-418; E-422; E-432; E-436; E-439 and E-441. Ref.10

Mutagenesis

457

1

S → A: Abolishes binding to TRAF2. Ref.8

Mutagenesis

601

1

C → A or S: Loss of deubiquitinating activity. Ref.6 Ref.7 Ref.11 Ref.22

Mutagenesis

871

1

H → N: Loss of deubiquitinating activity. Ref.8

Secondary structure

1

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956

Helix Strand Turn

Details...

Beta strand

130 – 134

5

Beta strand

136 – 139

4

Beta strand

141 – 149

9

Beta strand

154 – 157

4

Beta strand

163 – 167

5

Beta strand

169 – 171

3

Turn

191 – 193

3

Beta strand

194 – 197

4

Helix

199 – 201

3

Beta strand

202 – 204

3

Beta strand

235 – 240

6

Beta strand

243 – 253

11

Turn

259 – 261

3

Beta strand

264 – 272

9

Beta strand

278 – 280

3

Beta strand

283 – 285

3

Beta strand

293 – 298

6

Helix

299 – 301

3

Beta strand

302 – 304

3

Turn

463 – 465

3

Beta strand

466 – 468

3

Beta strand

474 – 478

5

Beta strand

480 – 482

3

Beta strand

486 – 492

7

Beta strand

495 – 497

3

Beta strand

501 – 508

8

Beta strand

514 – 518

5

Beta strand

531 – 535

5

Helix

536 – 538

3

Beta strand

539 – 541

3

Helix

584 – 586

3

Beta strand

588 – 591

4

Helix

601 – 611

11

Beta strand

612 – 614

3

Helix

615 – 617

3

Helix

618 – 622

5

Helix

633 – 642

10

Helix

645 – 650

6

Beta strand

652 – 654

3

Helix

656 – 669

14

Helix

682 – 690

9

Turn

691 – 694

4

Beta strand

699 – 704

6

Beta strand

710 – 713

4

Helix

730 – 741

12

Beta strand

743 – 747

5

Beta strand

750 – 755

6

Beta strand

760 – 764

5

Beta strand

773 – 775

3

Helix

778 – 780

3

Beta strand

781 – 784

4

Turn

789 – 791

3

Helix

800 – 802

3

Turn

806 – 811

6

Helix

818 – 824

7

Helix

828 – 830

3

Beta strand

859 – 868

10

Beta strand

871 – 877

7

Beta strand

879 – 881

3

Beta strand

885 – 889

5

Beta strand

905 – 908

4

Helix

911 – 914

4

Helix

920 – 925

6

Helix

928 – 930

3

Helix

935 – 940

6

Beta strand

944 – 948

5

Helix

950 – 952

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 1, 2000. Version 1. Checksum: 01831F9A83424631	FASTA	956	107,316
	10 20 30 40 50 60 MSSGLWSQEK VTSPYWEERI FYLLLQECSV TDKQTQKLLK VPKGSIGQYI QDRSVGHSRI 70 80 90 100 110 120 PSAKGKKNQI GLKILEQPHA VLFVDEKDVV EINEKFTELL LAITNCEERF SLFKNRNRLS 130 140 150 160 170 180 KGLQIDVGCP VKVQLRSGEE KFPGVVRFRG PLLAERTVSG IFFGVELLEE GRGQGFTDGV 190 200 210 220 230 240 YQGKQLFQCD EDCGVFVALD KLELIEDDDT ALESDYAGPG DTMQVELPPL EINSRVSLKV 250 260 270 280 290 300 GETIESGTVI FCDVLPGKES LGYFVGVDMD NPIGNWDGRF DGVQLCSFAC VESTILLHIN 310 320 330 340 350 360 DIIPALSESV TQERRPPKLA FMSRGVGDKG SSSHNKPKAT GSTSDPGNRN RSELFYTLNG 370 380 390 400 410 420 SSVDSQPQSK SKNTWYIDEV AEDPAKSLTE ISTDFDRSSP PLQPPPVNSL TTENRFHSLP 430 440 450 460 470 480 FSLTKMPNTN GSIGHSPLSL SAQSVMEELN TAPVQESPPL AMPPGNSHGL EVGSLAEVKE 490 500 510 520 530 540 NPPFYGVIRW IGQPPGLNEV LAGLELEDEC AGCTDGTFRG TRYFTCALKK ALFVKLKSCR 550 560 570 580 590 600 PDSRFASLQP VSNQIERCNS LAFGGYLSEV VEENTPPKME KEGLEIMIGK KKGIQGHYNS 610 620 630 640 650 660 CYLDSTLFCL FAFSSVLDTV LLRPKEKNDV EYYSETQELL RTEIVNPLRI YGYVCATKIM 670 680 690 700 710 720 KLRKILEKVE AASGFTSEEK DPEEFLNILF HHILRVEPLL KIRSAGQKVQ DCYFYQIFME 730 740 750 760 770 780 KNEKVGVPTI QQLLEWSFIN SNLKFAEAPS CLIIQMPRFG KDFKLFKKIF PSLELNITDL 790 800 810 820 830 840 LEDTPRQCRI CGGLAMYECR ECYDDPDISA GKIKQFCKTC NTQVHLHPKR LNHKYNPVSL 850 860 870 880 890 900 PKDLPDWDWR HGCIPCQNME LFAVLCIETS HYVAFVKYGK DDSAWLFFDS MADRDGGQNG 910 920 930 940 950 FNIPQVTPCP EVGEYLKMSL EDLHSLDSRR IQGCARRLLC DAYMCMYQSP TMSLYK
	Isoform 2 [UniParc]. Checksum: 0CCB3D21E2FF8851	FASTA	953	107,044
	10 20 30 40 50 60 MSSGLWSQEK VTSPYWEERI FYLLLQECSV TDKQTQKLLK VPKGSIGQYI QDRSVGHSRI 70 80 90 100 110 120 PSAKGKKNQI GLKILEQPHA VLFVDEKDVV EINEKFTELL LAITNCEERF SLFKNRNRLS 130 140 150 160 170 180 KGLQIDVGCP VKVQLRSGEE KFPGVVRFRG PLLAERTVSG IFFGVELLEE GRGQGFTDGV 190 200 210 220 230 240 YQGKQLFQCD EDCGVFVALD KLELIEDDDT ALESDYAGPG DTMQVELPPL EINSRVSLKV 250 260 270 280 290 300 GETIESGTVI FCDVLPGKES LGYFVGVDMD NPIGNWDGRF DGVQLCSFAC VESTILLHIN 310 320 330 340 350 360 DIIPESVTQE RRPPKLAFMS RGVGDKGSSS HNKPKATGST SDPGNRNRSE LFYTLNGSSV 370 380 390 400 410 420 DSQPQSKSKN TWYIDEVAED PAKSLTEIST DFDRSSPPLQ PPPVNSLTTE NRFHSLPFSL 430 440 450 460 470 480 TKMPNTNGSI GHSPLSLSAQ SVMEELNTAP VQESPPLAMP PGNSHGLEVG SLAEVKENPP 490 500 510 520 530 540 FYGVIRWIGQ PPGLNEVLAG LELEDECAGC TDGTFRGTRY FTCALKKALF VKLKSCRPDS 550 560 570 580 590 600 RFASLQPVSN QIERCNSLAF GGYLSEVVEE NTPPKMEKEG LEIMIGKKKG IQGHYNSCYL 610 620 630 640 650 660 DSTLFCLFAF SSVLDTVLLR PKEKNDVEYY SETQELLRTE IVNPLRIYGY VCATKIMKLR 670 680 690 700 710 720 KILEKVEAAS GFTSEEKDPE EFLNILFHHI LRVEPLLKIR SAGQKVQDCY FYQIFMEKNE 730 740 750 760 770 780 KVGVPTIQQL LEWSFINSNL KFAEAPSCLI IQMPRFGKDF KLFKKIFPSL ELNITDLLED 790 800 810 820 830 840 TPRQCRICGG LAMYECRECY DDPDISAGKI KQFCKTCNTQ VHLHPKRLNH KYNPVSLPKD 850 860 870 880 890 900 LPDWDWRHGC IPCQNMELFA VLCIETSHYV AFVKYGKDDS AWLFFDSMAD RDGGQNGFNI 910 920 930 940 950 PQVTPCPEVG EYLKMSLEDL HSLDSRRIQG CARRLLCDAY MCMYQSPTMS LYK

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification of the familial cylindromatosis tumor suppressor gene." Bignell G.R., Brown C., Biggs P.J., Lakhani S.R., Jones C., Hansen J., Blair E., Hofmann B., Siebert R., Turner G., Evans D.G., Schrander-Stumpel C., Beemer F.A., Van Den Ouweland A., Halley D., Delpech B., Cleveland M.G., Leigh I. , Leisti J., Rasmussen S., Wallace M.R., Fenske C., Banerjee P., Oiso N., Chaggar R., Merrett S., Leonard N., Huber M., Hohl D., Chapman P., Burn J., Swift S., Smith A., Ashworth A., Stratton M.R. Nat. Genet. 25:160-165(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, INVOLVEMENT IN FAMILIAL CYLINDROMATOSIS.
[2]	"Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro." Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O. DNA Res. 5:355-364(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Brain.
[3]	"Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones." Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T. DNA Res. 9:99-106(2002) [PubMed] [Europe PMC] [Abstract] Cited for: SEQUENCE REVISION.
[4]	"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). Tissue: Uterus.
[5]	"Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells." Zhang Q.-H., Ye M., Wu X.-Y., Ren S.-X., Zhao M., Zhao C.-J., Fu G., Shen Y., Fan H.-Y., Lu G., Zhong M., Xu X.-R., Han Z.-G., Zhang J.-W., Tao J., Huang Q.-H., Zhou J., Hu G.-X. , Gu J., Chen S.-J., Chen Z. Genome Res. 10:1546-1560(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 397-956. Tissue: Umbilical cord blood.
[6]	"CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members." Trompouki E., Hatzivassiliou E., Tsichritzis T., Farmer H., Ashworth A., Mosialos G. Nature 424:793-796(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH IKBKG/NEMO, MUTAGENESIS OF CYS-601.
[7]	"Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB." Brummelkamp T.R., Nijman S.M.B., Dirac A.M.G., Bernards R. Nature 424:797-801(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH IKBKG/NEMO, MUTAGENESIS OF CYS-601.
[8]	"The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination." Kovalenko A., Chable-Bessia C., Cantarella G., Israeel A., Wallach D., Courtois G. Nature 424:801-805(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH IKBKG/NEMO AND TRAF2, MUTAGENESIS OF SER-457 AND HIS-871.
[9]	"The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappaB activation by tumor necrosis factor." Regamey A., Hohl D., Liu J.W., Roger T., Kogerman P., Toftgaard R., Huber M. J. Exp. Med. 198:1959-1964(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH TRIP.
[10]	"Regulation of the deubiquitinating enzyme CYLD by IkappaB kinase gamma-dependent phosphorylation." Reiley W., Zhang M., Wu X., Granger E., Sun S.C. Mol. Cell. Biol. 25:3886-3895(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH TRAF2, ENZYME REGULATION, MUTAGENESIS OF SER-418; SER-422; SER-432; SER-436; SER-439; SER-441 AND SER-444, PHOSPHORYLATION AT SER-418.
[11]	"The tumor suppressor CYLD regulates entry into mitosis." Stegmeier F., Sowa M.E., Nalepa G., Gygi S.P., Harper J.W., Elledge S.J. Proc. Natl. Acad. Sci. U.S.A. 104:8869-8874(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF CYS-601, INTERACTION WITH PLK1, SUBCELLULAR LOCATION.
[12]	"The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response." Friedman C.S., O'Donnell M.A., Legarda-Addison D., Ng A., Cardenas W.B., Yount J.S., Moran T.M., Basler C.F., Komuro A., Horvath C.M., Xavier R., Ting A.T. EMBO Rep. 9:930-936(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBUNIT, INTERACTION WITH DDX58; MAVS; TBK1 AND IKKE.
[13]	"The tumor suppressor CYLD regulates microtubule dynamics and plays a role in cell migration." Gao J., Huo L., Sun X., Liu M., Li D., Dong J.T., Zhou J. J. Biol. Chem. 283:8802-8809(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[14]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[15]	"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, SUBCELLULAR LOCATION.
[16]	"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.
[17]	"Loss of the tumor suppressor CYLD enhances Wnt/beta-catenin signaling through K63-linked ubiquitination of Dvl." Tauriello D.V., Haegebarth A., Kuper I., Edelmann M.J., Henraat M., Canninga-van Dijk M.R., Kessler B.M., Clevers H., Maurice M.M. Mol. Cell 37:607-619(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH DVL1 AND DVL3.
[18]	"The CAP-Gly domain of CYLD associates with the proline-rich sequence in NEMO/IKKgamma." Saito K., Kigawa T., Koshiba S., Sato K., Matsuo Y., Sakamoto A., Takagi T., Shirouzu M., Yabuki T., Nunokawa E., Seki E., Matsuda T., Aoki M., Miyata Y., Hirakawa N., Inoue M., Terada T., Nagase T. , Kikuno R., Nakayama M., Ohara O., Tanaka A., Yokoyama S. Structure 12:1719-1728(2004) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 460-550, INTERACTION WITH IKBKG.
[19]	"Solution structure of the 1st and 2nd CAP-Gly domains in human cylindromatosis tumor suppressor CYLD." RIKEN structural genomics initiative (RSGI) Submitted (NOV-2004) to the PDB data bank Cited for: STRUCTURE BY NMR OF 125-304.
[20]	"Phenotype diversity in familial cylindromatosis: a frameshift mutation in the tumor suppressor gene CYLD underlies different tumors of skin appendages." Poblete Gutierrez P., Eggermann T., Hoeller D., Jugert F.K., Beermann T., Grussendorf-Conen E.-I., Zerres K., Merk H.F., Frank J. J. Invest. Dermatol. 119:527-531(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN FCYL, INVOLVEMENT IN BRSS.
[21]	"Identification of a recurrent mutation in the CYLD gene in Brooke-Spiegler syndrome." Scheinfeld N., Hu G., Gill M., Austin C., Celebi J.T. Clin. Exp. Dermatol. 28:539-541(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN BRSS.
[22]	"The structure of the CYLD USP domain explains its specificity for Lys63-linked polyubiquitin and reveals a B box module." Komander D., Lord C.J., Scheel H., Swift S., Hofmann K., Ashworth A., Barford D. Mol. Cell 29:451-464(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 583-956 IN COMPLEX WITH ZINC IONS, FUNCTION, ACTIVE SITE, MUTAGENESIS OF CYS-601, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION.
[23]	"A novel missense mutation in CYLD in a family with Brooke-Spiegler syndrome." Hu G., Oender M., Gill M., Aksakal B., Oeztas M., Guerer M.A., Celebi J.T. J. Invest. Dermatol. 121:732-734(2003) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT MFT1 GLY-747, VARIANT BRSS GLY-747.
[24]	"Two novel CYLD gene mutations in Chinese families with trichoepithelioma and a literature review of 16 families with trichoepithelioma reported in China." Liang Y.H., Gao M., Sun L.D., Liu L.J., Cui Y., Yang S., Fan X., Wang J., Xiao F.L., Zhang X.J. Br. J. Dermatol. 153:1213-1215(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN MFT1.
[25]	"Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlation." Bowen S., Gill M., Lee D.A., Fisher G., Geronemus R.G., Vazquez M.E., Celebi J.T. J. Invest. Dermatol. 124:919-920(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN BRSS.
[26]	"CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes." Young A.L., Kellermayer R., Szigeti R., Teszas A., Azmi S., Celebi J.T. Clin. Genet. 70:246-249(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN FCYL, INVOLVEMENT IN MFT1.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AJ250014 mRNA. Translation: CAB93533.1.
AB020656 mRNA. Translation: BAA74872.2. Different initiation.
BC012342 mRNA. Translation: AAH12342.1.
AF161542 mRNA. Translation: AAF29029.1. Frameshift.

IPI

IPI00106663.
IPI00456609.

RefSeq

NP_001035814.1. NM_001042355.1.
NP_001035877.1. NM_001042412.1.
NP_056062.1. NM_015247.2.

UniGene

Hs.578973.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1IXD	NMR	-	A	460-550	[»]
1WHL	NMR	-	A	125-206	[»]
1WHM	NMR	-	A	228-304	[»]
2VHF	X-ray	2.80	A/B	583-956	[»]

ProteinModelPortal

Q9NQC7.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9NQC7. 12 interactions.

MINT

MINT-6804518.

STRING

9606.ENSP00000308928.

Protein family/group databases

MEROPS

C67.001.

PTM databases

PhosphoSite

Q9NQC7.

Polymorphism databases

DMDM

51316104.

Proteomic databases

PaxDb

Q9NQC7.

PRIDE

Q9NQC7.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000311559; ENSP00000308928; ENSG00000083799.
ENST00000398568; ENSP00000381574; ENSG00000083799.
ENST00000427738; ENSP00000392025; ENSG00000083799.
ENST00000564326; ENSP00000454515; ENSG00000083799.
ENST00000569418; ENSP00000457576; ENSG00000083799.

GeneID

1540.

KEGG

hsa:1540.

UCSC

uc002egp.1. human.
uc002egq.1. human.

Organism-specific databases

CTD

1540.

GeneCards

GC16P050775.

HGNC

HGNC:2584. CYLD.

HPA

CAB011713.

MIM

132700. phenotype.
601606. phenotype.
605018. gene.
605041. phenotype.

neXtProt

NX_Q9NQC7.

Orphanet

211. Familial cylindromatosis.
867. Familial multiple trichoepithelioma.

PharmGKB

PA27084.

HUGE

Search...

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG313578.

HOGENOM

HOG000006796.

HOVERGEN

HBG051281.

InParanoid

Q9NQC7.

KO

K08601.

Enzyme and pathway databases

Pathway_Interaction_DB

nfkappabcanonicalpathway. Canonical NF-kappaB pathway.
tnfpathway. TNF receptor signaling pathway.

Reactome

REACT_6900. Immune System.

Gene expression databases

ArrayExpress

Q9NQC7.

Bgee

Q9NQC7.

CleanEx

HS_CYLD.

Genevestigator

Q9NQC7.

GermOnline

ENSG00000083799. Homo sapiens.

Family and domain databases

Gene3D

2.30.30.190. 3 hits.

InterPro

IPR000938. CAP-Gly_domain.
IPR018200. Pept_C19ubi-hydrolase_C_CS.
IPR001394. Peptidase_C19.
[Graphical view]

Pfam

PF01302. CAP_GLY. 3 hits.
PF00443. UCH. 1 hit.
[Graphical view]

SMART

SM01052. CAP_GLY. 3 hits.
[Graphical view]

SUPFAM

SSF74924. CAP-Gly_domain. 3 hits.

PROSITE

PS00845. CAP_GLY_1. 1 hit.
PS50245. CAP_GLY_2. 2 hits.
PS00972. UCH_2_1. 1 hit.
PS00973. UCH_2_2. False negative.
PS50235. UCH_2_3. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

Q9NQC7.

GenomeRNAi

1540.

NextBio

6377.

SOURCE

Search...

Entry information

Entry name

CYLD_HUMAN

Accession

Primary (citable) accession number: Q9NQC7
Secondary accession number(s): O94934 , Q7L3N6, Q96EH0, Q9NZX9

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 16, 2004
Last sequence update:	October 1, 2000
Last modified:	May 29, 2013
This is version 116 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.