ABRO1 promotes NLRP3 inflammasome activation through regulation of NLRP3 deubiquitination

The EMBO Journal
Guangming RenXiaoming Yang

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 inflamm...Continue Reading

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Citations

Nov 5, 2019·The FEBS Journal·Gloria Lopez-Castejon
Aug 4, 2020·Journal of Leukocyte Biology·Chloe M McKee, Rebecca C Coll
Sep 16, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Wei ZhaoJohn H Kehrl
Jul 12, 2020·International Journal of Molecular Sciences·Tiao Li, Chunbin Zou
Nov 4, 2020·International Journal of Molecular Sciences·Roya RasaeiSeok-Ho Hong
Jan 3, 2021·Cellular and Molecular Neurobiology·Fillipe M de AraújoMaria Trinidad Herrero
Dec 23, 2020·Life Sciences·Qihui GeJunping Zhang
Feb 5, 2021·Biomedicines·Baolong Liu, Jiujiu Yu
Jan 13, 2021·Cell Death and Differentiation·Peter E CockramDomagoj Vucic
Aug 28, 2020·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Pan SongChanghui Ge
Apr 15, 2021·Cellular & Molecular Immunology·Seungwha PaikEun-Kyeong Jo
Apr 25, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jun NiXuefeng Wu
Aug 11, 2021·Nature Communications·Ying QinWei Zhao
Aug 13, 2021·Frontiers in Immunology·Hua Bai, Qifang Zhang
Aug 28, 2021·International Journal of Molecular Sciences·Mahbuba AktherKwang-Ho Lee
Sep 15, 2021·Proceedings of the National Academy of Sciences of the United States of America·Fabian A FischerJelena S Bezbradica
Oct 8, 2021·Nature Communications·Tingting NiuBénédicte F Py

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