Five new CYLD mutations in skin appendage tumors and evidence that aspartic acid 681 in CYLD is essential for deubiquitinase activity.

Details

Serval ID
serval:BIB_29828FA514DD
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Five new CYLD mutations in skin appendage tumors and evidence that aspartic acid 681 in CYLD is essential for deubiquitinase activity.
Journal
Journal of Investigative Dermatology
Author(s)
Almeida S., Maillard C., Itin P., Hohl D., Huber M.
ISSN
1523-1747[electronic]
Publication state
Published
Issued date
2008
Volume
128
Number
3
Pages
587-593
Language
english
Abstract
Brooke-Spiegler syndrome, familial cylindromatosis, and familial trichoepithelioma are autosomal-dominant genetic predispositions for benign tumors of skin appendages caused by mutations in the CYLD gene localized on chromosome 16q12-q13. The encoded protein functions as ubiquitin-specific protease (UBP), which negatively regulates NF-kappaB and c-Jun N-terminal kinase (JNK) signaling. We investigated five families affected with these skin neoplasms and identified four premature stop codons and the novel missense mutation D681G in a family in which 11 of 12 investigated tumors were trichoepitheliomas. CYLD protein harboring this missense mutation had a significant reduced ability to inhibit TNF receptor-associated factor (TRAF)2- and TRAF6-mediated NF-kappaB activation, tumor necrosis factor-alpha (TNFalpha)-induced JNK signaling, and to deubiquitinate TRAF2. CYLD-D681G was coimmunoprecipitated by TRAF2, but was unable to cleave K63-linked polyubiquitin chains. Aspartic acid 681 is highly conserved in CYLD homologues and other members of the UBP family, but does not belong to the Cys and His boxes providing the CYLD catalytic triad (Cys601, His871, and Asp889). As reported previously, the homologous residue D295 of HAUSP/USP-7 forms a hydrogen bond with the C-terminal end of ubiquitin and is important for the enzymatic activity. These results underline that D681 in CYLD is required for cleavage of K63-linked polyubiquitin chains.
Keywords
Adult, Amino Acid Sequence, Biopsy, Carcinoma, Adenoid Cystic/genetics, Carcinoma, Adenoid Cystic/metabolism, Carcinoma, Skin Appendage/genetics, Carcinoma, Skin Appendage/metabolism, Cell Line, Tumor, Codon, Terminator, Female, Humans, Male, Molecular Sequence Data, Mutation, Missense, Pedigree, Skin Neoplasms/genetics, Skin Neoplasms/metabolism, TNF Receptor-Associated Factor 2/metabolism, TNF Receptor-Associated Factor 6/metabolism, Tumor Suppressor Proteins/genetics, Tumor Suppressor Proteins/metabolism, Ubiquitin/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
29/01/2009 22:14
Last modification date
20/08/2019 13:09
Usage data