Germ-Cell-Specific Inflammasome Component NLRP14 Negatively Regulates Cytosolic Nucleic Acid Sensing to Promote Fertilization.
Germ-Cell-Specific Inflammasome Component NLRP14 Negatively Regulates Cytosolic Nucleic Acid Sensing to Promote Fertilization.
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DOI：
10.1016/j.immuni.2017.03.020
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发表时间：
2017-04-18
期刊：
影响因子：
32.4
通讯作者：
Shapira SD
中科院分区：
文献类型：
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作者：
Abe T;Lee A;Sitharam R;Kesner J;Rabadan R;Shapira SD
核酸的胞质感测启动严格调控的程序以限制感染。卵母细胞受精代表了对外源性但非病原体来源的核酸的不适当反应将产生负面后果的情况。我们假设生殖细胞在稳定状态下表达核酸传感（NAS）的负调节因子，并应用集成的数据挖掘和功能基因组学方法来识别DNA和RNA传感的变阻器-炎性体组分NLRP 14。我们证明了NLRP 14与核酸传感途径物理相互作用，并靶向TBK 1（TANK结合激酶1）进行泛素化和降解。我们进一步定位了NLRP 14和TBK 1中介导抑制功能的结构域。最后，我们鉴定了一种与雄性不育相关的人类无义种系变异体，其导致NLRP 14功能丧失和对核酸的高反应性。这一发现指出了一种可能在受精中特别重要的核酸传感调节机制。核酸的胞质感测启动严格调控的程序以限制感染。受精代表了一种情况，即对外源但非病原体来源的DNA/RNA的不适当反应会产生负面后果。我们确定了一个进化上保守的免疫变阻器，以防止这种反应-一个功能，可能是有性生殖的先决条件。
Cytosolic sensing of nucleic acids initiates tightly regulated programs to limit infection. Oocyte fertilization represents a scenario when 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. This discovery points to a mechanism of nucleic acid sensing regulation that may be of particular importance in fertilization. Cytosolic sensing of nucleic acids initiates tightly regulated programs to limit infection. Fertilization represents a scenario when inappropriate responses to exogenous yet non-pathogen-derived DNA/RNA would have negative consequences. We identify an evolutionarily conserved immunological rheostat safeguarding against such responses – a function that may have been a prerequisite for sexual reproduction.
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影响因子：
7.3
作者：
Lupfer C;Kanneganti TD
通讯作者：
Kanneganti TD
影响因子：
32.4
作者：
de Almeida L;Khare S;Misharin AV;Patel R;Ratsimandresy RA;Wallin MC;Perlman H;Greaves DR;Hoffman HM;Dorfleutner A;Stehlik C
通讯作者：
Stehlik C
DOI：
10.1038/nri3921
发表时间：
2015-12
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
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影响因子：
16
作者：
Martinon, F;Burns, K;Tschopp, J
通讯作者：
Tschopp, J
NLRP4 通过泛素连接酶 DTX4 靶向激酶 TBK1 进行降解，从而负调节 I 型干扰素信号传导
影响因子：
30.5
作者：
通讯作者：
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