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.
Highlights
The ability to sense and respond to pathogens is central to the mammalian immune system
The linker in primate NLRP1, which is analogous to the N-terminal disordered region of NLRP1B that is cleaved by Lethal Factor (LF) protease, has undergone recurrent positive selection (Chavarrıa-Smith et al, 2016), or an excess of non-synonymous amino acid substitutions over what would be expected by neutral evolution (Kimura, 1983)
We chose to focus on the enterovirus genus of picornaviruses, as there is a deep and diverse collection of publicly available viral sequences within this genus due to their importance as human pathogens including coxsackieviruses, polioviruses, enterovirus D68, and human rhinovirus (HRV) (Blom et al, 1996; Pickett et al, 2012)
Summary
The ability to sense and respond to pathogens is central to the mammalian immune system. To ensure accurate discrimination of self and non-self, innate immune sensors detect broadly conserved microbial molecules such as bacterial flagellin or double-stranded RNA (Janeway, 1989) Such microbial patterns can be found on harmless and pathogenic microbes alike. Pathogen-specific activities such as toxins or effector enzymes have been shown to be targets of innate immune recognition (Jones et al, 2016; Mitchell et al, 2019; Vance et al, 2009) Such a system for detection, termed effector-trigged immunity (ETI), has been well-established in plants (Cui et al, 2015; Jones et al, 2016) and is emerging as an important means to allow the immune system to distinguish pathogens from harmless microbes in animals (Fischer et al, 2020; Jones et al, 2016)
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