The Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Immunity. 2012 Jun 29;36(6):933-46. doi: 10.1016/j.immuni.2012.03.025.
The mitochondrial protein MAVS (also known as IPS-1, VISA, and CARDIF) interacts with RIG-I-like receptors (RLRs) to induce type I interferon (IFN-I). NLRX1 is a mitochondrial nucleotide-binding, leucine-rich repeats (NLR)-containing protein that attenuates MAVS-RLR signaling. Using Nlrx1(-/-) cells, we confirmed that NLRX1 attenuated IFN-I production, but additionally promoted autophagy during viral infection. This dual function of NLRX1 paralleled the previously described functions of the autophagy-related proteins Atg5-Atg12, but NLRX1 did not associate with Atg5-Atg12. High-throughput quantitative mass spectrometry and endogenous protein-protein interaction revealed an NLRX1-interacting partner, mitochondrial Tu translation elongation factor (TUFM). TUFM interacted with Atg5-Atg12 and Atg16L1 and has similar functions as NLRX1 by inhibiting RLR-induced IFN-I but promoting autophagy. In the absence of NLRX1, increased IFN-I and decreased autophagy provide an advantage for host defense against vesicular stomatitis virus. This study establishes a link between an NLR protein and the viral-induced autophagic machinery via an intermediary partner, TUFM.
线粒体蛋白 MAVS（也称为 IPS-1、VISA 和 CARDIF）与 RIG-I 样受体（RLRs）相互作用，诱导 I 型干扰素（IFN-I）的产生。NLRX1 是一种线粒体核苷酸结合、富含亮氨酸重复（NLR）的蛋白，可减弱 MAVS-RLR 信号通路。使用 Nlrx1(-/-) 细胞，我们证实 NLRX1 减弱了 IFN-I 的产生，但在病毒感染期间还促进了自噬。NLRX1 的这种双重功能与先前描述的自噬相关蛋白 Atg5-Atg12 的功能平行，但 NLRX1 与 Atg5-Atg12 不相关。高通量定量质谱和内源性蛋白质-蛋白质相互作用揭示了一个 NLRX1 相互作用的伙伴，线粒体 Tu 翻译伸长因子（TUFM）。TUFM 与 Atg5-Atg12 和 Atg16L1 相互作用，并通过抑制 RLR 诱导的 IFN-I 但促进自噬来发挥与 NLRX1 相似的功能。在没有 NLRX1 的情况下，增加的 IFN-I 和减少的自噬为宿主防御水疱性口炎病毒提供了优势。本研究通过一个中间伙伴 TUFM，建立了 NLR 蛋白与病毒诱导的自噬机制之间的联系。
