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. 2019 Sep 18;10(10):692. doi: 10.1038/s41419-019-1937-y

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 7 — a M1-ubiquitylation-proficient cells: A20 protects cells from TNF-mediated apoptosis by antagonizing CYLD-mediated degradation of M1-ubiquitin chains. Binding of TNF to TNFR1 induces the formation of TNFR1 Complex I. The E3 ubiquitin ligases cIAP1/2 conjugate Complex I components with ubiquitin chains of different types, including K63-linked chains. The multiprotein E3 complex LUBAC docks on these newly formed K63-linked chains to further conjugate Complex I components with M1-linked (linear) ubiquitin chains; creating, in some cases, hybrid K63/M1 chains. Within minutes of TNF sensing, constitutively expressed A20 is recruited to Complex I via the binding of its ZF7 domain to ubiquitin chains of different types, including M1-linked chains. Recruited A20 promotes cell survival by antagonizing CYLD-mediated hydrolysis of the M1-linked ubiquitin chains in the complex. In conditions of A20 deficiency, CYLD dismantles the M1-linked ubiquitin network, ultimately inducing RIPK1 kinase-dependent and -independent apoptosis. b In absence of M1-ubiquitylation: A20 protects cells from TNF-induced apoptosis by deubiquitylating a yet to be identified substrate. Constitutively expressed A20 is still recruited to Complex I in absence of M1-ubiquitylation through ZF4/ZF7-mediated binding to the residual ubiquitin chains, potentially the K63-linked chains. Recruited A20 limits the extent of TNF-induced apoptosis by deubiquitylating unknown substrate(s). The DUB activity of A20 may counteract the K48-ubiquitin-mediated proteasomal degradation of a prosurvival molecule and/or the K63-ubiquitin-dependent stabilization of a prodeath signaling platform.