The SUMOylation of TAB2 mediated by TRIM60 inhibits MAPK/NF-κB activation and the innate immune response
Open Access
- 12 November 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cellular & Molecular Immunology
- Vol. 18 (8), 1981-1994
- https://doi.org/10.1038/s41423-020-00564-w
Abstract
Activation of the TAK1 signalosome is crucial for mediating the innate immune response to pathogen invasion and is regulated by multiple layers of posttranslational modifications, including ubiquitination, SUMOylation, and phosphorylation; however, the underlying molecular mechanism is not fully understood. In this study, TRIM60 negatively regulated the formation and activation of the TAK1 signalosome. Deficiency of TRIM60 in macrophages led to enhanced MAPK and NF-κB activation, accompanied by elevated levels of proinflammatory cytokines but not IFN-I. Immunoprecipitation-mass spectrometry assays identified TAB2 as the target of TRIM60 for SUMOylation rather than ubiquitination, resulting in impaired formation of the TRAF6/TAB2/TAK1 complex and downstream MAPK and NF-κB pathways. The SUMOylation sites of TAB2 mediated by TRIM60 were identified as K329 and K562; substitution of these lysines with arginines abolished the SUMOylation of TAB2. In vivo experiments showed that TRIM60-deficient mice showed an elevated immune response to LPS-induced septic shock and L. monocytogenes infection. Our data reveal that SUMOylation of TAB2 mediated by TRIM60 is a novel mechanism for regulating the innate immune response, potentially paving the way for a new strategy to control antibacterial immune responses.Keywords
Funding Information
- Ministry of Science and Technology of the People’s Republic of China (2016YFA0502203, 2016YFA0502201,2019YFA0110201, 2018YFE0204500,2018YFC1004601, 2019YFA0110203)
- National Natural Science Foundation of China (91740111, 81871232 and 31870881, 31870881)
- 1.3.5 project of disciplines of excellence, West China Hospital, Sichuan University
- Ministry of Science and Technology of the People’s Republic of China
- Ministry of Science and Technology of the People’s Republic of China
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