Diverse viral proteases activate the NLRP1 inflammasome

Abstract

The NLRP1 inflammasome is a multiprotein complex that is a potent activator of inflammation. Mouse NLRP1B can be activated through proteolytic cleavage by the bacterial Lethal Toxin (LeTx) protease, resulting in degradation of the N-terminal domains of NLRP1B and liberation of the bioactive C-terminal domain, which includes the caspase activation and recruitment domain (CARD). However, natural pathogen-derived effectors that can activate human NLRP1 have remained unknown. Here, we use an evolutionary model to identify several proteases from diverse picornaviruses that cleave human NLRP1 within a rapidly evolving region of the protein, leading to host-specific and virus-specific activation of the NLRP1 inflammasome. Our work demonstrates that NLRP1 acts as a 'tripwire' to recognize the enzymatic function of a wide range of viral proteases and suggests that host mimicry of viral polyprotein cleavage sites can be an evolutionary strategy to activate a robust inflammatory immune response.

Oxidized thioredoxin-1 restrains the NLRP1 inflammasome

“…At least three seemingly unrelated agents -the enteroviral 3C protease (8,9), long doublestranded RNA (dsRNA) (10), and DPP8/9 inhibitors (11)(12)(13)(14)(15)(16) -activate the human NLRP1 inflammasome. 3C protease cleaves within the disordered linker between the PYD and NACHT domains, creating an unstable neo-N-terminus that is degraded by the N-end rule proteasome pathway.…”

Running With Scissors: Evolutionary Conflicts Between Viral Proteases and the Host Immune System

“…Most picornaviruses have six or more 3C cleavage sites throughout the polyprotein ( Figure 1A ), and there is a preference to cleave between a glutamine (Q) in the P1 position and a small residue [e.g. glycine (G) or serine (S)] in the P1’ position ( Figure 3A ) ( 15 , 16 , 20 ). Likewise, coronaviruses (CoVs) have ten or more cleavage sites for the 3CL protease (also known as MPro or nsp5 in several CoVs including SARS-CoV-2) ( Figure 3B ) ( 17 , 18 , 21 ).…”

“…Names of viruses with human relevance or referenced throughout the text are listed next to their respective genus or singular node. The consensus enterovirus 3C cleavage motif (bottom) as was generated previously ( 15 ). The cleavage site is shown flanked by four amino acids upstream (labeled P4 through P1) and four amino acids downstream (labeled P1’ through P4’).…”

“…In addition to homology between the proteases themselves, the positions and sequences of the polyprotein cleavage motifs are often similar between members of the same viral family. Indeed, this conservation of polyprotein cleavage motifs has made it possible to compile sequences surrounding the cleavage site from genome sequences alone to generate a consensus motif for the viral protease that can be used to predict host and viral targets ( 15 , 20 , 32 , 33 ) ( Figure 3A ). These consensus motifs are often generated using many diverse viruses, relying on the assumption that protease sequence specificity is well conserved among virus species.…”

“…Interestingly, despite the evolutionary constraint to maintain cleavage across multiple sites in the polyprotein, virus-encoded proteases are substantially divergent across viruses ( Figure 3 ). For instance, picornavirus 3C proteases can share less than 20% amino acid sequence identity, despite sharing an overall similar fold and many homologous cleavage sites ( 15 ). Similar evolutionary distances are observed with other families of proteases, including Coronaviridae 3CL and Flaviviridae NS3 ( Figure 3 ).…”