Germ-Cell-Specific Inflammasome Component NLRP14 Negatively Regulates Cytosolic Nucleic Acid Sensing to Promote Fertilization

Cytosolic sensing of nucleic acids initiates tightly regulated programs to limit infection. Oocyte fertilization represents a scenario wherein inappropriate responses to exogenous yet non-pathogen-derived nucleic acids would have negative consequences. We hypothesized that germ cells express negative regulators of nucleic acid sensing (NAS) in steady state and applied an integrated data-mining and functional genomics approach to identify a rheostat of DNA and RNA sensing—the inflammasome component NLRP14. We demonstrated that NLRP14 interacted physically with the nucleic acid sensing pathway and targeted TBK1 (TANK binding kinase 1) for ubiquitination and degradation. We further mapped domains in NLRP14 and TBK1 that mediated the inhibitory function. Finally, we identified a human nonsense germline variant associated with male sterility that results in loss of NLRP14 function and hyper-responsiveness to nucleic acids. The discovery points to a mechanism of nucleic acid sensing regulation that may be of particular importance in fertilization. •Identified NLRP14 as a germ-cell-specific inhibitor of cytosolic nucleic acid sensing•NLRP14 interacts with signaling components that regulate the cGAS/RIG-I axis•NLRP14 targets TBK1 for degradation to inhibit DNA and RNA sensing•SNPs associated with male sterility result in loss of NLRP14 function Cytosolic sensing of nucleic acids limits infection, but fertilization represents a scenario when responses to exogenous, non-pathogen-derived nucleic acids would be detrimental. Abe et al. identify NLRP14 as an evolutionarily conserved immunological rheostat that safeguards against such responses, which may have been a prerequisite for the evolution of sexual reproduction.