Diverse Scaffolds Facilitate NLRP3 Clustering and Inflammasome Formation in Response to Perturbations in Cell Homeostasis

TL;DR

The NLRP3 inflammasome responds to various cellular disturbances by forming molecular scaffolds that help activate the immune system.

Contribution

The paper proposes that diverse molecular scaffolds facilitate NLRP3 clustering and inflammasome formation in response to cellular perturbations.

Findings

NLRP3 responds to changes in lipid membranes, protein localization, and organelle function.

Molecular scaffolds recruit NLRP3 and promote its clustering and inflammasome assembly.

NLRP3 acts as an adaptable sensor integrating multiple danger signals.

Abstract

A central component of innate immunity, the NLRP3 inflammasome is a multiprotein complex formed in response to a chemically and morphologically diverse spectrum of stimuli. Despite extensive investigation, no single ligand or signal has emerged to account for this breadth of activation. Here, we review the landscape of NLRP3 activation across subcellular compartments and examine how this process is shaped by a network of interacting partners. Recent studies suggest that NLRP3 responds to cellular perturbations, such as changes in lipid membrane composition, protein localization, or organelle function. We propose that distinct upstream cues converge to generate diverse molecular scaffolds that recruit NLRP3. The NLRP3‐scaffold interactions promote NLRP3 clustering, destabilize its autoinhibited conformation, and drive assembly of the inflammasome. NLRP3 is thus an adaptable sensor, equipped with versatile molecular interactions that allow it to integrate multiple danger signals into inflammasome activation.

NLRP3, a cytosolic innate immune sensor, responds to diverse activators that perturb cellular homeostasis. These disturbances generate molecular scaffolds that, through binding partners such as nucleic acids, lipids, and proteins, recruit and concentrate NLRP3. Scaffold‐mediated NLRP3 clustering promotes NLRP3 inflammasome assembly.

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