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Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains.
<div class='caption-title'>CYLD is a Lys63-DUB reliant on extra-catalytic domains and phosphorylation for full activity</div>
<div class='caption-title'>CAP-Gly domains 2 and 3 of CYLD bind Ub</div>
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
OpenAccess logo Cell Rep 37 109777 (2021)
Cited: 15 times
EuropePMC logo PMID: 34610306

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.

Articles - 7owc mentioned but not cited (1)

  1. Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains. 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. Cell Rep 37 109777 (2021)


Reviews citing this publication (8)

  1. Deubiquitinases in cell death and inflammation. Newton K, Gitlin AD. Biochem J 479 1103-1119 (2022)
  2. The Potential of Cylindromatosis (CYLD) as a Therapeutic Target in Oxidative Stress-Associated Pathologies: A Comprehensive Evaluation. Huang Z, Tan Y. Int J Mol Sci 24 8368 (2023)
  3. CYLD in health and disease. Marín-Rubio JL, Raote I, Inns J, Dobson-Stone C, Rajan N. Dis Model Mech 16 dmm050093 (2023)
  4. Cell Death-Related Ubiquitin Modifications in Inflammatory Syndromes: From Mice to Men. Peltzer N, Annibaldi A. Biomedicines 10 1436 (2022)
  5. Cellular Deubiquitylating Enzyme: A Regulatory Factor of Antiviral Innate Immunity. Long S, Yang L, Dang W, Xin S, Jiang M, Zhang W, Li J, Wang Y, Zhang S, Lu J. Front Microbiol 12 805223 (2021)
  6. Deubiquitinases in cancer. Dewson G, Eichhorn PJA, Komander D. Nat Rev Cancer 23 842-862 (2023)
  7. Mechanisms underlying linear ubiquitination and implications in tumorigenesis and drug discovery. Li J, Liu S, Li S. Cell Commun Signal 21 340 (2023)
  8. Regulation of apoptosis by ubiquitination in liver cancer. Li Y, Zhu J, Yu Z, Zhai F, Li H, Jin X. Am J Cancer Res 13 4832-4871 (2023)

Articles citing this publication (6)

  1. Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin. Spaan AN, Neehus AL, Laplantine E, Staels F, Ogishi M, Seeleuthner Y, Rapaport F, Lacey KA, Van Nieuwenhove E, Chrabieh M, Hum D, Migaud M, Izmiryan A, Lorenzo L, Kochetkov T, Heesterbeek DAC, Bardoel BW, DuMont AL, Dobbs K, Chardonnet S, Heissel S, Baslan T, Zhang P, Yang R, Bogunovic D, Wunderink HF, Haas PA, Molina H, Van Buggenhout G, Lyonnet S, Notarangelo LD, Seppänen MRJ, Weil R, Seminario G, Gomez-Tello H, Wouters C, Mesdaghi M, Shahrooei M, Bossuyt X, Sag E, Topaloglu R, Ozen S, Leavis HL, van Eijk MMJ, Bezrodnik L, Blancas Galicia L, Hovnanian A, Nassif A, Bader-Meunier B, Neven B, Meyts I, Schrijvers R, Puel A, Bustamante J, Aksentijevich I, Kastner DL, Torres VJ, Humblet-Baron S, Liston A, Abel L, Boisson B, Casanova JL. Science 376 eabm6380 (2022)
  2. Genotoxicity-Stimulated and CYLD-Driven Malignant Transformation. Erol A. Cancer Manag Res 14 2339-2356 (2022)
  3. Letter IKK-mediated CYLD phosphorylation and cellular redox activity. Erol A. Mol Med 28 14 (2022)
  4. MALT1-dependent cleavage of CYLD promotes NF-κB signaling and growth of aggressive B-cell receptor-dependent lymphomas. Minderman M, Lantermans HC, Grüneberg LJ, Cillessen SAGM, Bende RJ, van Noesel CJM, Kersten MJ, Pals ST, Spaargaren M. Blood Cancer J 13 37 (2023)
  5. Mechanism of client selection by the protein quality-control factor UBE2O. Yip MCJ, Sedor SF, Shao S. Nat Struct Mol Biol 29 774-780 (2022)
  6. The roles of long non-coding RNAs in the necroptotic signaling of colon cancer cells. Bozgeyik E, Bagis H, Bozgeyik I, Kocahan S. Mol Biol Rep 50 5021-5028 (2023)


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