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

Harvard

Elliott, PR, Leske, D, Wagstaff, J, Schlicher, L, Berridge, G, Maslen, S, Timmermann, F, Ma, B, Fischer, R, Freund, SMV, Komander, D & Gyrd-Hansen, M 2021, 'Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains', Cell Reports, vol. 37, no. 1, 109777. https://doi.org/10.1016/j.celrep.2021.109777

APA

Elliott, P. R., Leske, D., Wagstaff, J., Schlicher, L., Berridge, G., Maslen, S., Timmermann, F., Ma, B., Fischer, R., Freund, S. M. V., Komander, D., & Gyrd-Hansen, M. (2021). Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains. Cell Reports, 37(1), [109777]. https://doi.org/10.1016/j.celrep.2021.109777

Vancouver

Elliott PR, Leske D, Wagstaff J, Schlicher L, Berridge G, Maslen S et al. Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains. Cell Reports. 2021;37(1). 109777. https://doi.org/10.1016/j.celrep.2021.109777

Author

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. / Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains. In: Cell Reports. 2021 ; Vol. 37, No. 1.

Bibtex

@article{a650ea066bd245c1aa40d97b3f8300ce,
title = "Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains",
abstract = "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.",
keywords = "CAP-Gly domain, CYLD, deubiquitinase, DUB, immune receptor signaling, inflammation, LUBAC, phosphorylation, TNF, ubiquitin chain",
author = "Elliott, {Paul R.} and Derek Leske and Jane Wagstaff and Lisa Schlicher and Georgina Berridge and Sarah Maslen and Frederik Timmermann and Biao Ma and Roman Fischer and Freund, {Stefan M.V.} and David Komander and Mads Gyrd-Hansen",
year = "2021",
doi = "10.1016/j.celrep.2021.109777",
language = "English",
volume = "37",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",

}

RIS

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