Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains
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Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains. / Elliott, Paul R.; Leske, Derek; Wagstaff, Jane; Schlicher, Lisa; Berridge, Georgina; Maslen, Sarah; Timmermann, Frederik; Ma, Biao; Fischer, Roman; Freund, Stefan M.V.; Komander, David; Gyrd-Hansen, Mads.
In: Cell Reports, Vol. 37, No. 1, 109777, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains
AU - Elliott, Paul R.
AU - Leske, Derek
AU - Wagstaff, Jane
AU - Schlicher, Lisa
AU - Berridge, Georgina
AU - Maslen, Sarah
AU - Timmermann, Frederik
AU - Ma, Biao
AU - Fischer, Roman
AU - Freund, Stefan M.V.
AU - Komander, David
AU - Gyrd-Hansen, Mads
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - CAP-Gly domain
KW - CYLD
KW - deubiquitinase
KW - DUB
KW - immune receptor signaling
KW - inflammation
KW - LUBAC
KW - phosphorylation
KW - TNF
KW - ubiquitin chain
U2 - 10.1016/j.celrep.2021.109777
DO - 10.1016/j.celrep.2021.109777
M3 - Journal article
C2 - 34610306
AN - SCOPUS:85117755236
VL - 37
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 1
M1 - 109777
ER -
ID: 284197526