The NLRP3-inflammasome as a sensor of organelle dysfunction

Abstract

Diverse pathogen- and damage-associated stresses drive inflammation via activation of the multimolecular NLRP3-inflammasome complex. How the effects of diverse stimuli are integrated by the cell to regulate NLRP3 has been the subject of intense research, and yet an accepted unifying hypothesis for the control of NLRP3 remains elusive. Here, we review the literature on the effects of NLRP3-activating stimuli on subcellular organelles and conclude that a shared feature of NLRP3-activating stresses is an organelle dysfunction. In particular, we propose that the endosome may be more important than previously recognized as a signal-integrating hub for NLRP3 activation in response to many stimuli and may also link to the dysfunction of other organelles. In addition, NLRP3-inflammasome-activating stimuli trigger diverse posttranslational modifications of NLRP3 that are important in controlling its activation. Future research should focus on how organelles respond to specific NLRP3-activating stimuli, and how this relates to posttranslational modifications, to delineate the organellar control of NLRP3.

Figure 1.

The canonical pathway of NLRP3–inflammasome activation. Priming stimuli such as LPS drive NF-κB–dependent expression of NLRP3 and pro-IL-1β, as well as NLRP3 licensing. NLRP3 is composed of an LRR, NACHT, and PYD domain. Numerous PTMs have been described that promote either activation or inhibition of NLRP3, including phosphorylation (P), ubiquitination (Ub), and sumoylation (S). Following the priming step, a broad spectrum of PAMP or DAMP stimuli triggers NLRP3 activation. Active NLRP3 oligomerizes and forms an inflammasome complex by nucleating the adaptor protein ASC to form a speck, leading to the recruitment and activation of the inflammasome effector protein caspase-1. Caspase-1 processes pro-IL-1β and pro-IL-18 into their active forms. Caspase-1 also cleaves gasdermin D (GSDMD), which forms pores in the membrane that may serve as the conduit for IL-1β release, as well as leading to pyroptotic cell death. The noncanonical and alternative pathways of NLRP3 activation are not shown. GSDMD-FL, GMDSD full length. GSDMD-N, GMDSD N-terminus. CARD, caspase activation and recruitment domain.

Figure 2.

Organelle localization and activation of NLRP3. NLRP3–inflammasome activation occurs in response to multiple stimuli, with the common feature being organelle stress and dysfunction. Indeed, NLRP3-activating stimuli induce some or all of the following: ER stress, MAM formation, mitochondrial ROS production and mtDNA release, dispersal of the TGN, lysosomal rupture, and disruption to endosomal pH. NLRP3-activating stimuli are also reported to trigger NLRP3 recruitment to MAMs, mitochondria, the TGN, and endosomes, suggesting that organelles may serve as both sensor and platform for NLRP3 activation.

Figure 3.

Endosome dysfunction may promote activation of NLRP3. Stimuli that activate the NLRP3–inflammasome (1) cause endosomal stress and dysfunction (2). Such endosomal dysfunction results in impaired recycling of proteins such as TGN38/46 to the TGN. Under conditions of endosomal stress, we propose that NLRP3 is recruited to the endosomal membrane, which may be driven in part by association with the inositol lipid PtdIns4P (3). Thus, the endosome membrane may serve as a platform for NLRP3 recruitment and subsequent inflammasome activation.