Inhibition of IRE1\u03b1 RNase activity reduces NLRP3 inflammasome assembly and processing of pro-IL1\u03b2

Aaron Talty,Mila Ljujic,Adrienne M Gorman,Matthew D Griffin,Katarzyna Mnich,Dagmar Quandt,Serika D Naicker,Qingping Zeng,John B Patterson,Shane Deegan,Afshin Samali,Susan E Logue

doi:10.1038/s41419-019-1847-z

Abstract

The inflammasome is a multiprotein complex assembled in response to Pathogen Associated Molecular Patterns (PAMPs) and Danger Associated Molecular Patterns (DAMPs). Inflammasome activation occurs through a two-step mechanism, with the first signal facilitating priming of inflammasome components while the second signal triggers complex assembly. Once assembled, the inflammasome recruits and activates pro-caspase-1, which in turn processes pro-interleukin (IL)-18 and pro-IL-1β into their bio-active forms. Owing to its key role in the regulation of innate immune responses, the inflammasome has emerged as a therapeutic target for the treatment of inflammatory conditions. In this study we demonstrate that IRE1α, a key component of the Unfolded Protein Response, contributes to assembly of the NLRP3 inflammasome. Blockade of IRE1α RNase signaling lowered NLRP3 inflammasome assembly, caspase-1 activation and pro-IL-1β processing. These results underscore both the importance and potential therapeutic relevance of targeting IRE1α signaling in conditions of excessive inflammasome formation.

Highlights

Protein folding and processing of transmembrane and secretory proteins occur within the endoplasmic reticulum (ER)
Classically inositol-requiring enzyme 1α (IRE1α) activation is associated with resolution of ER stress via activation of the adaptive, pro-survival unfolded protein response (UPR)
An important role for IRE1α signaling is emerging within the innate immune system where it has been linked to the function of several cell types including dendritic cells, macrophages, and natural killer cells[13]

Summary

Introduction

Protein folding and processing of transmembrane and secretory proteins occur within the endoplasmic reticulum (ER). The accumulation of unfolded/misfolded proteins activates three ER-anchored transmembrane receptors—inositol-requiring enzyme 1α (IRE1α)[1,2], protein kinase RNA (PKR)-like ER kinase (PERK)[3], and activating transcription factor-6 (ATF6)4—. IRE1α, a bifunctional transmembrane protein comprised of both a serine/threonine kinase domain and an endoribonuclease (RNase) domain, is the most evolutionarily conserved UPR sensor present in all eukaryotes. Similar to PERK and ATF6, the N-terminus of IRE1α juts into the ER lumen where, under nonstress conditions, it associates with the ER chaperone glucose-regulated protein 78 (Grp78)[6]. Accumulation of unfolded proteins initiates Grp[78] dissociation from IRE1α permitting IRE1α dimerization and trans-autophosphorylation leading to activation of its RNase domain. IRE1α RNase activity has two principal outputs; splicing of a 26-nucleotide intron from X-box binding protein 1 (XBP1) mRNA7 and IRE1αdependent decay of mRNA (RIDD), the sequence specific

Methods

Results

Conclusion