Article Metrics


Online attention

Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains

DOI: 10.1016/j.celrep.2021.109777 DOI Help

Authors: Paul R. Elliott (MRC Laboratory of Molecular Biology; University of Oxford) , Derek Leske (Ludwig Institute for Cancer Research, University of Oxford) , Jane Wagstaff (MRC Laboratory of Molecular Biology) , Lisa Schlicher (Ludwig Institute for Cancer Research, University of Oxford) , Georgina Berridge (Target Discovery Institute, University of Oxford) , Sarah Maslen (MRC Laboratory of Molecular Biology) , Frederik Timmermann (Ludwig Institute for Cancer Research, University of Oxford) , Biao Ma (Ludwig Institute for Cancer Research, University of Oxford) , Roman Fischer (Target Discovery Institute, University of Oxford) , Stefan M. V. Freund (MRC Laboratory of Molecular Biology) , David Komander (MRC Laboratory of Molecular Biology; The Walter and Eliza Hall Institute of Medical Research; University of Melbourne) , Mads Gyrd-Hansen (Ludwig Institute for Cancer Research, University of Oxford; University of Copenhagen)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Reports , VOL 37

State: Published (Approved)
Published: October 2021

Open Access Open Access

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.

Journal Keywords: CYLD; deubiquitinase; DUB; ubiquitin chain; CAP-Gly domain; phosphorylation; immune receptor signaling; TNF; inflammation; LUBAC

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography

Added On: 06/10/2021 08:41


Discipline Tags:

Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)