Shutting down innate immune responses during fertilization

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Science Signaling  02 May 2017:
Vol. 10, Issue 477, eaan5400
DOI: 10.1126/scisignal.aan5400

The inflammasome component NLRP14 inhibits the nucleic acid sensing pathway during fertilization.

The sensing of cytosolic nucleic acids stimulates the production of type I interferons (IFNs) as part of the innate immune response. Whereas the sensor RIG-I detects viral, but not host, RNA in the cytosol, the enzyme cyclic GMP-AMP synthase (cGAS) stimulates IFN production in response to either self or nonself cytosolic DNA (see Barber). During fertilization, sperm cell–derived DNA becomes exposed in the oocyte cytoplasm, which prompted Abe et al. to screen for germ cell–specific factors that inhibit nucleic acid sensing and thus block an immune response during fertilization. Twenty candidate genes were identified whose expression was decreased after fertilization had occurred. Overexpression of these genes in a reporter cell line expressing cGAS and its effector STING identified the inflammasome component NLRP14 as a potent inhibitor of nucleic acid sensing. Knockdown of NLRP14 in cells resulted in increased nucleic acid signaling (by either RIG-I or cGAS) and enhanced antiviral immunity. Coimmunoprecipitation studies showed that NLRP14 interacted with components of both the RIG-I and cGAS pathways and that it inhibited activation of the kinase TBK1, which is common to both pathways and activates the transcription factors required for type I IFN production. The binding of NLRP14 to TBK1, which required the N-terminal domains of NLRP14, resulted in the polyubiquitylation and degradation of the kinase. A single nucleotide polymorphism in sterile men with spermatogenic failure results in the generation of the truncated mutant protein K108X-NLRP14. In transfected cells, K108X-NLRP14 failed to associate with TBK1 and was less efficient than wild-type NLRP14 in inhibiting TBK1 activity, which resulted in increased IFN production. Together, these data suggest that NLRP14 inhibits nucleic acid sensing to prevent the IFN response from being triggered during fertilization.

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