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Immunity. 2017 Apr 18;46(4):621-634. doi: 10.1016/j.immuni.2017.03.020.

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

Author information

1
Department of Systems Biology, Columbia University, New York, NY 10032, USA; Department of Microbiology and Immunology, Columbia University, New York, NY 10032, USA.
2
Department of Systems Biology, Columbia University, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University, New York, NY 10032, USA.
3
Department of Systems Biology, Columbia University, New York, NY 10032, USA; Department of Microbiology and Immunology, Columbia University, New York, NY 10032, USA. Electronic address: ss4197@columbia.edu.

Abstract

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.

KEYWORDS:

DNA/RNA sensing; RIG-I; STING; TBK1; fertilization; inflammasome; innate immunity; nucleic acid sensing; regulation

PMID:
28423339
PMCID:
PMC5674777
DOI:
10.1016/j.immuni.2017.03.020
[Indexed for MEDLINE]
Free PMC Article

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