Cytosolic peptide accumulation activates the NLRP1 and CARD8 inflammasomes

Abstract

NLRP1 and CARD8 are related sensors that form inflammasomes, but the danger signals that they detect are not fully established. These proteins undergo autoproteolysis, generating repressive N-terminal (NT) and inflammatory C-terminal (CT) fragments. The proteasome-mediated degradation of the NT releases the CT from autoinhibition, but the CT is then sequestered in a complex with the full-length sensor and DPP9. Here, we show that cytosolic peptide accumulation activates these inflammasomes. We found that a diverse array of peptides accelerates NT degradation, and those with N-terminal XP sequences also destabilize the ternary complexes. Peptides interfere with many biological processes, including protein folding. We show that unrelated agents that disrupt protein folding also induce NT degradation, but do not cause inflammasome activation because DPP9 sequesters the CT fragments in the absence of XP peptides. Overall, these results indicate that NLRP1 and CARD8 detect protein misfolding that is associated with peptide accumulation.

Effector-Triggered Immunity

“…Like NLRP1, CARD8 is also activated by DPP8/9 inhibitors and therefore may function to guard DPP8/9 (117). CARD8 is also activated by reductive stress and peptide accumulation (105,106). The threshold for CARD8 activation by peptide accumulation appears to be lower than that for NLRP1.…”

“…To date, virulence factors that block DPP8/9 have not been identified, but future studies may shed light on this intriguing possibility. Additionally, small-molecule inducers of reductive stress or peptide accumulation have been shown to promote NLRP1 activation and pyroptosis (105,106). These findings suggest that NLRP1 may also guard the cellular redox state and protein homeostasis (105)(106)(107).…”

“…Additionally, small-molecule inducers of reductive stress or peptide accumulation have been shown to promote NLRP1 activation and pyroptosis (105,106). These findings suggest that NLRP1 may also guard the cellular redox state and protein homeostasis (105)(106)(107). However, whether pathogens trigger NLRP1 activation via induction of reductive stress and peptide accumulation remains to be shown.…”

Inflammasomes in epithelial innate immunity: front line warriors

“…More recently, cytosolic peptide accumulation in combination with reductive stress was found to strongly activate NLRP1 activation. It will be important to develop assays to assess reductive stress and peptide accumulation during the maintenance of skin homeostasis while under pathogen attack [160,161]. NLRP10 is a new inflammasome sensor in the skin that has been recently described.…”