Structural basis for thioredoxin-mediated suppression of NLRP1 inflammasome
Zhang, Z. et al. (2023) Structural basis for thioredoxin-mediated suppression of NLRP1 inflammasome. Nature. 622, 188-194. DOI: 10.1038/s41586-023-06532-4
Plant and animal innate immune systems use cytosolic nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) to control and sense pathogen invasion and danger signals. The inflammasome is a supramolecular complex formed by NLR family pyrin domain-containing protein 1 (NLRP1). NLRP1 is expressed in primary immune cells and epithelial cells, as well as other cell types. Hyperactivation of NLRP1 has been linked to the development of autoinflammatory diseases and cancers.
The human NLRP1 protein specifically has an N-terminal pyrin domain, a central NOD, disordered linked region, leucine-rich repeat domain, function to find domain and a C-terminal caspase activation and recruitment domain. 3C viral proteases from enterovirus and coxsackievirus cleave NLRP1 at the disordered linker region and are identified pathogenic factors for NLRP1 activation. Following the proteolytic cleavage, proteasomal degradation of the N-terminal fragment of NLRP1 by way of the N-degron pathway releases the C-terminal UPA-CARD fragment. The UPA-CARD fragment is then oligomerized and recruits ASC or procaspase-1. The entire process is regulated by ubiquitination, sequestration of the UPA-CARD fragment by dipeptidyl peptidases 8 and 9 and autocatalytic cleavage in the function to find domain. Other microbial activators also control NLRP1 activity.
This study sought to understand the mechanism that underlies regulation and activation of human NLRP1 using cryo-electron microscopy analysis and mutagenesis studies. Researchers found that ubiquitously expressed endogenous thioredoxin (TRX) binds to NLRP1 creating a boomerang-shaped complex. Structural and mutagenesis analyses suggest that the oxidized form of TRX is more favorable for NLRP1 binding compared to the reduced form. Additionally, cellular assays demonstrated that TRX is a direct suppressor of the NLRP1 inflammasome. As our understanding of the interaction between the TRX and innate immune systems evolves, this interaction is unveiling new pathways for the development of potential therapeutic interventions.
Keywords: Human NLRP1, innate immune system, inflammasome, proteases, TRX.
