10779/crick.12681785.v1
Peter Draber
Peter
Draber
Sebastian Kupka
Sebastian
Kupka
Matthias Reichert
Matthias
Reichert
Helena Draberova
Helena
Draberova
Elodie Lafont
Elodie
Lafont
Diego de Miguel
Diego
de Miguel
Lisanne Spilgies
Lisanne
Spilgies
Silvia Surinova
Silvia
Surinova
Lucia Taraborrelli
Lucia
Taraborrelli
Torsten Hartwig
Torsten
Hartwig
Eva Rieser
Eva
Rieser
Luigi Martino
Luigi
Martino
Katrin Rittinger
Katrin
Rittinger
Henning Walczak
Henning
Walczak
LUBAC-recruited CYLD and A20 regulate gene activation and cell death by exerting opposing effects on linear ubiquitin in signaling complexes
The Francis Crick Institute
2020
Cell Death
Cell Line
DNA-Binding Proteins
Deubiquitinating Enzyme CYLD
Humans
Immunoprecipitation
Intracellular Signaling Peptides and Proteins
Nuclear Proteins
Signal Transduction
Transcriptional Activation
Transduction, Genetic
Tumor Necrosis Factor alpha-Induced Protein 3
Tumor Suppressor Proteins
Ubiquitin
Ubiquitin-Protein Ligase Complexes
Ubiquitination
Rittinger U117565398
0601 Biochemistry and Cell Biology
2020-07-21 10:11:13
Journal contribution
https://crick.figshare.com/articles/journal_contribution/LUBAC-recruited_CYLD_and_A20_regulate_gene_activation_and_cell_death_by_exerting_opposing_effects_on_linear_ubiquitin_in_signaling_complexes/12681785
Ubiquitination and deubiquitination are crucial for assembly and disassembly of signaling complexes. LUBAC-generated linear (M1) ubiquitin is important for signaling via various immune receptors. We show here that the deubiquitinases CYLD and A20, but not OTULIN, are recruited to the TNFR1- and NOD2-associated signaling complexes (TNF-RSC and NOD2-SC), at which they cooperate to limit gene activation. Whereas CYLD recruitment depends on its interaction with LUBAC, but not on LUBAC's M1-chain-forming capacity, A20 recruitment requires this activity. Intriguingly, CYLD and A20 exert opposing effects on M1 chain stability in the TNF-RSC and NOD2-SC. While CYLD cleaves M1 chains, and thereby sensitizes cells to TNF-induced death, A20 binding to them prevents their removal and, consequently, inhibits cell death. Thus, CYLD and A20 cooperatively restrict gene activation and regulate cell death via their respective activities on M1 chains. Hence, the interplay between LUBAC, M1-ubiquitin, CYLD, and A20 is central for physiological signaling through innate immune receptors.