Guo Haitao, König Renate, Deng Meng, Riess Maximilian, Mo Jinyao, Zhang Lu, Petrucelli Alex, Yoh Sunnie M, Barefoot Brice, Samo Melissa, Sempowski Gregory D, Zhang Aiping, Colberg-Poley Anamaris M, Feng Hui, Lemon Stanley M, Liu Yong, Zhang Yanping, Wen Haitao, Zhang Zhigang, Damania Blossom, Tsao Li-Chung, Wang Qi, Su Lishan, Duncan Joseph A, Chanda Sumit K, Ting Jenny P-Y
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Cell Host Microbe. 2016 Apr 13;19(4):515-528. doi: 10.1016/j.chom.2016.03.001.
Understanding the negative regulators of antiviral immune responses will be critical for advancing immune-modulated antiviral strategies. NLRX1, an NLR protein that negatively regulates innate immunity, was previously identified in an unbiased siRNA screen as required for HIV infection. We find that NLRX1 depletion results in impaired nuclear import of HIV-1 DNA in human monocytic cells. Additionally, NLRX1 was observed to reduce type-I interferon (IFN-I) and cytokines in response to HIV-1 reverse-transcribed DNA. NLRX1 sequesters the DNA-sensing adaptor STING from interaction with TANK-binding kinase 1 (TBK1), which is a requisite for IFN-1 induction in response to DNA. NLRX1-deficient cells generate an amplified STING-dependent host response to cytosolic DNA, c-di-GMP, cGAMP, HIV-1, and DNA viruses. Accordingly, Nlrx1(-/-) mice infected with DNA viruses exhibit enhanced innate immunity and reduced viral load. Thus, NLRX1 is a negative regulator of the host innate immune response to HIV-1 and DNA viruses.
了解抗病毒免疫反应的负调控因子对于推进免疫调节抗病毒策略至关重要。NLRX1是一种对先天免疫起负调控作用的NLR蛋白，之前在一项无偏向性的siRNA筛选中被确定为HIV感染所必需的因子。我们发现，在人类单核细胞中，NLRX1的缺失会导致HIV-1 DNA的核输入受损。此外，观察到NLRX1会减少对HIV-1逆转录DNA的I型干扰素（IFN-I）和细胞因子反应。NLRX1使DNA感应衔接蛋白STING与TANK结合激酶1（TBK1）相互作用受阻，而TBK1是DNA诱导IFN-1所必需的。缺乏NLRX1的细胞会对胞质DNA、环二鸟苷酸（c-di-GMP）、环磷鸟苷酸（cGAMP）、HIV-1和DNA病毒产生增强的STING依赖性宿主反应。因此，感染DNA病毒的Nlrx1(-/-)小鼠表现出增强的先天免疫和降低的病毒载量。所以，NLRX1是宿主对HIV-1和DNA病毒先天免疫反应的负调控因子。
