title: LUBAC-Recruited CYLD and A20 Regulate Gene Activation and Cell Death by Exerting Opposing Effects on Linear Ubiquitin in Signaling Complexes.
abstract: 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.
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Draber
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kupka
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Matthias
authors.initials: M
authors.lastname: Reichert
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Helena
authors.initials: H
authors.lastname: Draberova
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Elodie
authors.initials: E
authors.lastname: Lafont
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Diego
authors.initials: D
authors.lastname: de Miguel
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Lisanne
authors.initials: L
authors.lastname: Spilgies
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Surinova
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Lucia
authors.initials: L
authors.lastname: Taraborrelli
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Torsten
authors.initials: T
authors.lastname: Hartwig
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Eva
authors.initials: E
authors.lastname: Rieser
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW7 1AA, UK.
authors.forename: Luigi
authors.initials: L
authors.lastname: Martino
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW7 1AA, UK.
authors.forename: Katrin
authors.initials: K
authors.lastname: Rittinger
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. Electronic address: h.walczak@ucl.ac.uk.
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
mesh_terms: D016923:Cell Death / Q000502:physiology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D000074749:Deubiquitinating Enzyme CYLD; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology*; D014161:Transduction, Genetic; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D043743:Ubiquitin-Protein Ligase Complexes; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3