Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
PLoS Pathog. 2011 May;7(5):e1002057. doi: 10.1371/journal.ppat.1002057. Epub 2011 May 19.
The signaling of Toll-like receptors (TLRs) is the host's first line of defense against microbial invasion. The mitochondrion is emerging as a critical platform for antiviral signal transduction. The regulatory role of mitochondria for TLR signaling remains to be explored. Here, we show that the mitochondrial outer-membrane protein MARCH5 positively regulates TLR7 signaling. Ectopic expression or knockdown of MARCH5 enhances or impairs NF-κB-mediated gene expression, respectively. MARCH5 interacts specifically with TANK, and this interaction is enhanced by R837 stimulation. MARCH5 catalyzes the K63-linked poly-ubiquitination of TANK on its Lysines 229, 233, 280, 302 and 306, thus impairing the ability of TANK to inhibit TRAF6. Mislocalization of MARCH5 abolishes its action on TANK, revealing the critical role of mitochondria in modulating innate immunity. Arguably, this represents the first study linking mitochondria to TLR signaling.
Toll 样受体（TLRs）的信号转导是宿主抵御微生物入侵的第一道防线。线粒体作为抗病毒信号转导的关键平台正在逐渐显现。线粒体对 TLR 信号转导的调节作用仍有待探索。在这里，我们发现线粒体外膜蛋白 MARCH5 正向调节 TLR7 信号转导。MARCH5 的异位表达或敲低分别增强或损害 NF-κB 介导的基因表达。MARCH5 特异性地与 TANK 相互作用，并且这种相互作用在 R837 刺激下增强。MARCH5 催化 TANK 的赖氨酸 229、233、280、302 和 306 上的 K63 连接多泛素化，从而削弱了 TANK 抑制 TRAF6 的能力。MARCH5 的定位错误使其无法对 TANK 发挥作用，揭示了线粒体在调节先天免疫中的关键作用。可以说，这是第一项将线粒体与 TLR 信号转导联系起来的研究。
