AI Article Synopsis
- - SERTAD1 is identified as an adaptor protein that regulates the K63-linked polyubiquitination of NLRP3, playing a key role in inflammasome activation by interfering with the Cullin1 E3 ubiquitin ligase interaction.
- - The interaction between SERTAD1 and NLRP3 increases following inflammasome activation and is essential for proper secretion of inflammatory cytokines IL-1β and IL-18, as well as the cleavage of gasdermin D.
- - Mice lacking SERTAD1 exhibit less severe inflammation in response to certain conditions, and SERTAD1 expression is found to be elevated in patients with autoimmune diseases, highlighting its importance in NLRP3
Article Abstract
We here demonstrate that SERTAD1 is an adaptor protein responsible for the regulation of lysine 63 (K63)-linked NLRP3 polyubiquitination by the Cullin1 E3 ubiquitin ligase upon inflammasome activation. SERTAD1 specifically binds to NLRP3 but not to other inflammasome sensors. This endogenous interaction increases after inflammasome activation, interfering with the interaction between NLRP3 and Cullin1. Interleukin (IL)-1β and IL-18 secretion, as well as the cleavage of gasdermin D, are decreased in SERTAD1 knockout bone-marrow-derived macrophages, together with reduced formation of the NLRP3 inflammasome complex. Additionally, SERTAD1-deficient mice show attenuated severity of monosodium-uric-acid-induced peritonitis and experimental autoimmune encephalomyelitis. Analysis of public datasets indicates that expression of SERTAD1 mRNA is significantly increased in the patients of autoimmune diseases. Thus, our findings uncover a function of SERTAD1 that specifically reduces Cullin1-mediated NLRP3 polyubiquitination via direct binding to NLRP3, eventually acting as a crucial factor to regulate the initiation of NLRP3-mediated inflammasome activation.
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| http://dx.doi.org/10.1016/j.celrep.2024.113752 | DOI Listing |
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