Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains.
Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains.
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DOI：
10.1016/j.celrep.2021.109777
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发表时间：
2021-10-05
期刊：
影响因子：
8.8
通讯作者：
Gyrd-Hansen M
中科院分区：
文献类型：
--
作者：
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
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. CAP-Gly domains in CYLD are ubiquitin (Ub)-binding domains CAP-Gly3 is indispensable for full CYLD catalytic activity Phosphorylation of Ser568 activates CYLD Lys63-Ub DUB activity Ub binding and phosphorylation impacts CYLD regulation of receptor signaling Elliott et al. show that the catalytic activity of CYLD relies on ubiquitin binding via its CAP-Gly3 domain, and they identify a phosphorylation switch that stimulates cleavage of Lys63-Ub. Cellular work provides evidence that phosphorylated CYLD balances Lys63- and Met1-linked polyubiquitin at receptor signaling complexes to promote LUBAC signaling.
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影响因子：
16
作者：
Elliott, Paul R.;Leske, Derek;Hrdinka, Matous;Bagola, Katrin;Fiil, Berthe K.;McLaughlin, Stephen H.;Wagstaff, Jane;Volkmar, Norbert;Christianson, John C.;Kessler, Benedikt M.;Freund, Stefan M. V.;Komander, David;Gyrd-Hansen, Mads
通讯作者：
Gyrd-Hansen, Mads
影响因子：
16.6
作者：
Kazimierczuk, Krzysztof;Orekhov, Vladislav Yu.
通讯作者：
Orekhov, Vladislav Yu.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
2.7
作者：
DELAGLIO, F;GRZESIEK, S;BAX, A
通讯作者：
BAX, A
影响因子：
8.8
作者：
Hrdinka M;Fiil BK;Zucca M;Leske D;Bagola K;Yabal M;Elliott PR;Damgaard RB;Komander D;Jost PJ;Gyrd-Hansen M
通讯作者：
Gyrd-Hansen M