Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains.
Cell Line, Tumor
Crystallography, X-Ray
Deubiquitinating Enzyme CYLD
/ antagonists & inhibitors
Endopeptidases
/ chemistry
Humans
Nod2 Signaling Adaptor Protein
/ genetics
Phosphorylation
Polyubiquitin
/ metabolism
Protein Binding
Protein Domains
Protein Structure, Tertiary
RNA Interference
RNA, Small Interfering
/ metabolism
Signal Transduction
Tumor Necrosis Factor-alpha
/ metabolism
Ubiquitin
/ metabolism
CAP-Gly domain
CYLD
DUB
LUBAC
TNF
deubiquitinase
immune receptor signaling
inflammation
phosphorylation
ubiquitin chain
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
05 10 2021
05 10 2021
Historique:
received:
18
06
2021
revised:
25
08
2021
accepted:
09
09
2021
entrez:
5
10
2021
pubmed:
6
10
2021
medline:
17
2
2022
Statut:
ppublish
Résumé
Non-degradative ubiquitin chains and phosphorylation events govern signaling responses by innate immune receptors. The deubiquitinase CYLD in complex with SPATA2 is recruited to receptor signaling complexes by the ubiquitin ligase LUBAC and regulates Met1- and Lys63-linked polyubiquitin and receptor signaling outcomes. Here, we investigate the molecular determinants of CYLD activity. We reveal that two CAP-Gly domains in CYLD are ubiquitin-binding domains and demonstrate a requirement of CAP-Gly3 for CYLD activity and regulation of immune receptor signaling. Moreover, we identify a phosphorylation switch outside of the catalytic USP domain, which activates CYLD toward Lys63-linked polyubiquitin. The phosphorylated residue Ser568 is a novel tumor necrosis factor (TNF)-regulated phosphorylation site in CYLD and works in concert with Ser418 to enable CYLD-mediated deubiquitination and immune receptor signaling. We propose that phosphorylated CYLD, together with SPATA2 and LUBAC, functions as a ubiquitin-editing complex that balances Lys63- and Met1-linked polyubiquitin at receptor signaling complexes to promote LUBAC signaling.
Identifiants
pubmed: 34610306
pii: S2211-1247(21)01231-6
doi: 10.1016/j.celrep.2021.109777
pmc: PMC8511506
pii:
doi:
Substances chimiques
NOD2 protein, human
0
Nod2 Signaling Adaptor Protein
0
RNA, Small Interfering
0
Tumor Necrosis Factor-alpha
0
Ubiquitin
0
Polyubiquitin
120904-94-1
Endopeptidases
EC 3.4.-
OTULIN protein, human
EC 3.4.-
CYLD protein, human
EC 3.4.19.12
Deubiquitinating Enzyme CYLD
EC 3.4.19.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
109777Subventions
Organisme : Wellcome Trust
ID : 215612/Z/19/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_U105184326
Pays : United Kingdom
Organisme : Medical Research Council
ID : U105192732
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R008582/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 102894/Z/13/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_U105192732
Pays : United Kingdom
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests D.K. is on the Scientific Advisory Board of BioTheryX, Inc. The remaining authors declare no competing interests.
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