<35> NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations
NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations
Leanne Mortimer, France Moreau, Justin A MacDonald & Kris Chadee
2016, Nature Immunology 17, 1176–1186
Speaker: Zhong-Hong Wu (吳忠鴻) Time: 13:00~14:00, May 17, 2017
Commentator: Shu-Ying Wang, Ph.D. (王淑鶯老師) Place: Room 601
Abstract:
Inflammasomes are positioned to rapidly escalate the intensity of inflammation by activating interleukin (IL)-1b, IL-18 and cell death by pyroptosis. Mutations in NLRP3-encoding residues adjacent to Ser295 have been linked to the inflammatory disease Cryopyrin associated periodic syndromes (CAPS), which has activating mutation to activate caspase-1. Furthermore, the NLRP3 inflammasome is involved in the pathogenesis of numerous wide-spread chronic diseases, such as vascular disease, non-alcoholic fatty liver disease, obesity and type II diabetes. Protein kinase A (PKA) is a serine/threonine kinase that regulates a diverse number of pathways by modulating gene transcription and post-translational signaling. PKA is promptly activated by increasing intracellular concentrations of cyclic adenylyl monophosphate (cAMP). Prostaglandin E2 (PGE2) is a lipid mediator that regulates the progression of inflammation. It signals through four different receptors of the E-prostanoid (EP) family: EP1, EP2, EP3 and EP4. Both EP2 and EP4 activate adenylyl cyclases and turn on PKA via cAMP. In this article, the authors find out that PGE2 instantly and selectively inhibits the NLRP3 inflammasome activation via the EP4-cAMP-PKA pathway. PKA directly phosphorylates NLRP3 and turns off the ATPase, which suppresses the activation of NLRP3 inflammasome. Ser295 is essential for rapid cAMP-induced inhibition, but CAPS mutations linked to Ser295 are unresponsive to cAMP. These data suggest that negative regulation at Ser295 is critical for restraining the NLRP3 inflammasome and identify a molecular basis for CAPS-associated NLRP3 mutations.
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