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AA467197 controls the hyperactivation of the NLRP3 inflammasome during infection

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  • Corresponding author: xiap@pku.edu.cn (P.X.)
    1. Protein AA467197 is an essential regulator in chronic infections.

      AA467197 is positively involved in the establishment of hyperactivated NLRP3 inflammasome.

      AA467197 binds to GSDMD to limit its cleavage and allows persistent IL-1β secretion and cell viability.

      AA467197 deficiency exacerbates immune responses.

  • The hyperactivation of NLRP3 plays an essential role during infections, in which case a small portion of GSDMD is processed to become active and IL-1β is secreted for a long duration. However, the mechanism underlying NLRP3 hyperactivation remains unclear. Here we took use of the CRISPR/Cas9 technology to screen for genes involved in NLRP3 hyperactivation. We discovered that AA467197 suppresses the NLRP3 inflammasome to a hyperactivation state, and without affecting the canonical NLRP3 inflammasome activation. During infections caused by low doses of pathogens, AA467197 deficient cells have elevated rates of cell death compared with wild-type controls. Mechanistically, AA467197 binds to GSDMD and hinders its processing by the oligomerized caspase-1. Cells deficient for AA467197 undergo canonical NLRP3 inflammasome activation when encountering low-dose infections, leading to severe GSDMD cleavage and cell pyroptosis. Our results uncover a molecular mechanism for the exquisite regulation of the NLRP3 inflammasome in a hyperactivated state, which might be useful for further clinical treatment of infections.
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  • Cite this article:

    Liu Q., Li W., Qian Y., et al., (2023). AA467197 controls the hyperactivation of the NLRP3 inflammasome during infection. The Innovation Life 1(1), 100012. https://doi.org/10.59717/j.xinn-life.2023.100012
    Liu Q., Li W., Qian Y., et al., (2023). AA467197 controls the hyperactivation of the NLRP3 inflammasome during infection. The Innovation Life 1(1), 100012. https://doi.org/10.59717/j.xinn-life.2023.100012

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