Exploring inflammasome activation and targeted inhibition

Introduction

Inflammasomes are cytosolic multi-protein complexes that form in response to a wide range of pathogens, tissue damage, and other harmful stimuli. Members of the family of NOD-like receptors (NLRs) sense these pathogen and danger-associated molecular patterns, triggering innate immune responses.

NLRP3 Overview

NLRP3 is a well-studied NLR whose activation by a broad spectrum of stimuli leads to inflammasome formation and pyroptosis. Yet, the mechanisms inducing NLRP3 activation and the way how antagonistic small molecules counteract its function remain poorly understood.

Recent Discoveries

Just recently, we have determined the cryo-electron microscopy structures of full-length human NLRP3 in its inactive form and bound to the inhibitor CRID3. Native NLRP3 is a decamer composed of homodimers of intertwined LRR domains that assemble back-to-back as pentamers.

Key Findings

We made the surprising finding that the effector pyrin domain is shielded inside the decamer cage, providing a safeguard mechanism against accidental activation.

Proposed Research Endeavour

To obtain insights into the activation mechanism of NLRP3 and the molecular formation of the inflammasome, I propose a challenging and pioneering endeavour:

1. Employ biochemical, biophysical, and structural analyses to resolve the structure of activated NLRP3 associated with lipid membranes.
2. Unravel its regulation by post-translational modifications.
3. Design specific inhibitors for targeted protein degradation.
4. Explore filamentous seeds for the maturation of Caspase-1 and Alzheimer’s disease forming amyloid-beta fibrils.

Broader Implications

Further, transferring our knowledge of CRID3-mediated NLRP3 inhibition to other NLRs such as NLRP12 and NLRP1 will shed light on their mechanism of action and open new avenues for directed targeting.

Conclusion

Collectively, this work will uncover fundamental molecular principles of inflammasome activation and the mode of action of anti-inflammatory drugs. I foresee that these insights will open a wide field for the development of NLR-specific inhibitors as new medicines.