ABRO1 promotes NLRP3 inflammasome activation through regulation of NLRP3 deubiquitination

ABRO1 promotes NLRP3 inflammasome activation through regulation of NLRP3 deubiquitination

February 20, 2019

Abstract

Deubiquitination of NLRP3 has been suggested to contribute to inflammasome activation, but the roles and molecular mechanisms are still unclear. We here demonstrate that ABRO1, a subunit of the BRISC deubiquitinase complex, is necessary for optimal NLRP3‐ASC complex formation, ASC oligomerization, caspase‐1 activation, and IL‐1β and IL‐18 production upon treatment with NLRP3 ligands after the priming step, indicating that efficient NLRP3 activation requires ABRO1. Moreover, we report that ABRO1 deficiency results in a remarkable attenuation in the syndrome severity of NLRP3‐associated inflammatory diseases, including MSU‐ and Alum‐induced peritonitis and LPS‐induced sepsis in mice. Mechanistic studies reveal that LPS priming induces ABRO1 binding to NLRP3 in an S194 phosphorylation‐dependent manner, subsequently recruiting the BRISC to remove K63‐linked ubiquitin chains of NLRP3 upon stimulation with activators. Furthermore, deficiency of BRCC3, the catalytically active component of BRISC, displays similar phenotypes to ABRO1 knockout mice. Our findings reveal an ABRO1‐mediated regulatory signaling system that controls activation of the NLRP3 inflammasome and provide novel potential targets for treating NLRP3‐associated inflammatory diseases.

Authors: Guangming Ren, View ORCID ProfileXuanyi Zhang, View ORCID ProfileYang Xiao, Wen Zhang, Yu Wang, Wenbing Ma, Xiaohan Wang, Pan Song, Lili Lai, Hui Chen, Yiqun Zhan, Jianhong Zhang, View ORCID ProfileMiao Yu, Changhui Ge, View ORCID ProfileChangyan Li, View ORCID ProfileRonghua Yin, Xiaoming Yang

Influence Factor: 10.557

Citation: EMBO J 38, (2019).

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