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Review
. 2022 Nov;19(11):1201-1214.
doi: 10.1038/s41423-022-00922-w. Epub 2022 Sep 20.

How location and cellular signaling combine to activate the NLRP3 inflammasome

Anil Akbal #  1 , Alesja Dernst #  1 , Marta Lovotti #  1 , Matthew S J Mangan #  1 , Róisín M McManus #  1   2 , Eicke Latz #  3   4   5   6
Affiliations
Review

How location and cellular signaling combine to activate the NLRP3 inflammasome

Anil Akbal et al. Cell Mol Immunol. 2022 Nov.

Abstract

NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) is a cytosolic innate immune sensor of cellular stress signals, triggered by infection and sterile inflammation. Upon detection of an activating stimulus, NLRP3 transitions from an inactive homo-oligomeric multimer into an active multimeric inflammasome, which promotes the helical oligomeric assembly of the adaptor molecule ASC. ASC oligomers provide a platform for caspase-1 activation, leading to the proteolytic cleavage and activation of proinflammatory cytokines in the IL-1 family and gasdermin D, which can induce a lytic form of cell death. Recent studies investigating both the cellular requirement for NLRP3 activation and the structure of NLRP3 have revealed the complex regulation of NLRP3 and the multiple steps involved in its activation. This review presents a perspective on the biochemical and cellular processes controlling the assembly of the NLRP3 inflammasome with particular emphasis on structural regulation and the role of organelles. We also highlight the latest research on metabolic control of this inflammatory pathway and discuss promising clinical targets for intervention.

Keywords: Inflammasome; Localization; Mechanism; NLRP3; Regulation; Structure.

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Conflict of interest statement

EL is the co-founder and consultant of IFM Therapeutics, DiosCure Therapeutics, and Odyssey Therapeutics. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
NLRP3 cellular localization. The cellular localization of NLRP3 has a significant impact on its activity and effector function. NLRP3 has been found in close proximity to mitochondria, the endoplasmic reticulum, and the Golgi apparatus. Changes to and within these organelles can directly contribute to NLRP3 activation, although the reciprocal effect of NLRP3 on these structures remains to be fully established
Fig. 2
Fig. 2
Posttranslational modification (PTM) of NLRP3. NLRP3 activity is controlled by various PTMs, including the ubiquitination of lysine residues and the phosphorylation of serine and tyrosine residues, which either enhance (top panel) or reduce (lower panel) NLRP3 assembly and activity. PTMs are regulated by a variety of enzymes, and the regulation of these enzymes may represent therapeutic strategies for diseases involving NLRP3
See this image and copyright information in PMC

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