Abstract
The NLRP3 inflammasome is a multimeric protein complex that cleaves caspase-1 and the pro-inflammatory cytokines interleukin 1 beta (IL-1β) and IL-18. Dysregulated NLRP3 inflammasome signalling is linked to several chronic inflammatory and autoimmune conditions; thus, understanding the activation mechanisms of the NLRP3 inflammasome is essential. Studies over the past few years have implicated vital roles for distinct intracellular organelles in both the localisation and assembly of the NLRP3 inflammasome. However, conflicting reports exist. Prior to its activation, NLRP3 has been shown to be resident in the endoplasmic reticulum (ER) and cytosol, although, upon activation, the NLRP3 inflammasome has been shown to assemble in the cytosol, mitochondria, and mitochondria-associated ER membranes by different reports. Finally, very recent work has suggested that NLRP3 may be localised on or adjacent to the Golgi apparatus and that release of mediators from this organelle may contribute to inflammasome assembly. Therefore, NLRP3 may be strategically placed on or in close proximity to these subcellular compartments to both sense danger signals originating from these organelles and use the compartment as a scaffold to assemble the complex. Understanding where and when NLRP3 inflammasome assembly occurs may help identify potential targets for treatment of NLRP3-related disorders.
Highlights
Inflammasomes are multimeric protein complexes composed of typically a Nod-like receptor (NLR) or absent in myeloma 2 (AIM2), the adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC), and the effector protease caspase-1
We review recent literature focusing on the roles that mitochondria, endoplasmic reticulum (ER), and Golgi play in the localisation, assembly, and activation of the NLRP3 inflammasome
Cellular reactive oxygen species (ROS) was initially shown to activate the NLRP3 inflammasome in an NAPDH-dependent manner; further studies showed that ROS generated by the mitochondria is sufficient to lead to NLRP3 activation[26,38,39]
Summary
Inflammasomes are multimeric protein complexes composed of typically a Nod-like receptor (NLR) or absent in myeloma 2 (AIM2), the adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC), and the effector protease caspase-1. Cellular localisation of NLRP3 and ASC Studies conducted almost a decade ago suggested NLRP3 inflammasome localisation on mitochondria and mitochondriaassociated ER membranes (MAMs)[26]. The localisation of NLRP3 on or in close vicinity to mitochondria offers an obvious advantage to the cell as any disturbance in cellular homeostasis leading to mitochondrial dysfunction would result in efficient sensing and activation of NLRP3.
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