Abstract

Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) constitute the largest family of pattern recognition receptors. These receptors are master regulators of innate immunity. Recently, PELO-driven ATPase activation of NLRs was demonstrated as a critical step in NLR activation. Linkage studies in human with various inherited autoinflammatory conditions have revealed an extensive array of mutations and polymorphisms within NLRs. However, the precise mechanisms by which genetic variations in NLR genes contribute to disease onset remain largely elusive. Here we comprehensively analyze dozens of naturally occurring mutations across multiple human NLRs, and demonstrate that NLRs harboring pathogenic mutations in their NACHT domain--not those with non-pathogenic variants--exhibit spontaneous PELO-independent ATPase activation. This aberrant activation triggers corresponding NLR to mediate inflammatory responses. Thus, bypassing the PELO-checkpoint for ATPase activation is a major disease-causing mechanism underlying NLR mutations. Furthermore, quantifying this aberrant ATPase activation could serve as an assessment tool for classifying the pathogenesis of NLR-associated diseases.