1. Academic Validation
  2. AKT Regulates NLRP3 Inflammasome Activation by Phosphorylating NLRP3 Serine 5

AKT Regulates NLRP3 Inflammasome Activation by Phosphorylating NLRP3 Serine 5

  • J Immunol. 2020 Oct 15;205(8):2255-2264. doi: 10.4049/jimmunol.2000649.
Wei Zhao 1 2 3 4 Chong-Shan Shi 2 Kathleen Harrison 2 Il-Young Hwang 2 Neel R Nabar 2 Min Wang 3 John H Kehrl 5
Affiliations

Affiliations

  • 1 Department of Prosthodontics, College of Stomatology, Xi'an Jiaotong University, Xi'an 710004, China.
  • 2 B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
  • 3 State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, China; and.
  • 4 Department of Prosthodontics, National Clinical Research Center for Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
  • 5 B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Jkehrl@niaid.nih.gov.
Abstract

The cytosolic pattern recognition receptor NLRP3 senses host-derived danger signals and certain microbe-derived products in both humans and rodents. NLRP3 activation assembles an inflammasome complex that contains the adapter proteins ASC and Caspase-1, whose activation triggers the maturation and release of the proinflammatory cytokines IL-1β and IL-18. S5 phosphorylation of NLRP3 prevents its oligomerization and activation, whereas dephosphorylation of this residue by the Phosphatase PP2A allows NLRP3 activation. However, the protein kinase that mediates NLRP3 S5 phosphorylation is unknown. In this study, we show that Akt associates with NLRP3 and phosphorylates it on S5, limiting NLRP3 oligomerization. This phosphorylation event also stabilizes NLRP3 by reducing its ubiquitination on lysine 496, which inhibits its proteasome-mediated degradation by the E3 Ligase Trim31. Pharmacologic manipulation of Akt kinase activity reciprocally modulates NLRP3 inflammasome-mediated IL-1β production. Inhibition of Akt reduced IL-1β production following the i.p. injection of LPS into mice. We propose that Akt, Trim31, and PP2A together modulate NLRP3 protein levels and the tendency to oligomerize, thereby setting a tightly regulated threshold for NLRP3 activation.

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