Laboratory of Molecular Signalling, Division of Oral Biology and Medicine, University of California Los Angeles School of Dentistry, Los Angeles, California, United States of America.
PLoS One. 2010 Feb 11;5(2):e9172. doi: 10.1371/journal.pone.0009172.
The recognition of nucleic acids by the innate immune system during viral infection results in the production of type I interferons and the activation of antiviral immune responses. The RNA helicases RIG-I and MDA-5 recognize distinct types of cytosolic RNA species and signal through the mitochondrial protein MAVS to stimulate the phosphorylation and activation of the transcription factors IRF3 and IRF7, thereby inducing type I interferon expression. Alternatively, the activation of NF-kappaB leads to proinflammatory cytokine production. The function of MAVS is dependent on both its C-terminal transmembrane (TM) domain and N-terminal caspase recruitment domain (CARD). The TM domain mediates MAVS dimerization in response to viral RNA, allowing the CARD to bind to and activate the downstream effector TRAF3. Notably, dimerization of the MAVS CARD alone is sufficient to activate IRF3, IRF7, and NF-kappaB. However, TRAF3-deficient cells display only a partial reduction in interferon production in response to RNA virus infection and are not defective in NF-kappaB activation. Here we find that the related ubiquitin ligase TRAF5 is a downstream target of MAVS that mediates both IRF3 and NF-kappaB activation. The TM domain of MAVS allows it to dimerize and thereby associate with TRAF5 and induce its ubiquitination in a CARD-dependent manner. Also, NEMO is recruited to the dimerized MAVS CARD domain in a TRAF3 and TRAF5-dependent manner. Thus, our findings reveal a possible function for TRAF5 in mediating the activation of IRF3 and NF-kappaB downstream of MAVS through the recruitment of NEMO. TRAF5 may be a key molecule in the innate response against viral infection.
在病毒感染过程中，固有免疫系统识别核酸会导致 I 型干扰素的产生和抗病毒免疫反应的激活。RIG-I 和 MDA-5 这两种 RNA 解旋酶识别不同类型的细胞质 RNA 种类，并通过线粒体蛋白 MAVS 发出信号，刺激转录因子 IRF3 和 IRF7 的磷酸化和激活，从而诱导 I 型干扰素的表达。或者，NF-κB 的激活会导致促炎细胞因子的产生。MAVS 的功能依赖于其 C 端跨膜 (TM) 结构域和 N 端半胱天冬酶募集结构域 (CARD)。TM 结构域介导 MAVS 对病毒 RNA 的二聚化，允许 CARD 结合并激活下游效应物 TRAF3。值得注意的是，MAVS CARD 的二聚化本身足以激活 IRF3、IRF7 和 NF-κB。然而，TRAF3 缺陷细胞在 RNA 病毒感染时干扰素的产生仅部分减少，并且 NF-κB 的激活没有缺陷。在这里，我们发现相关的泛素连接酶 TRAF5 是 MAVS 的下游靶标，它介导 IRF3 和 NF-κB 的激活。MAVS 的 TM 结构域允许它二聚化，从而与 TRAF5 结合，并以 CARD 依赖的方式诱导其泛素化。此外，NEMO 以 TRAF3 和 TRAF5 依赖的方式被募集到二聚化的 MAVS CARD 结构域。因此，我们的研究结果揭示了 TRAF5 在通过募集 NEMO 介导 MAVS 下游的 IRF3 和 NF-κB 激活中的可能功能。TRAF5 可能是固有抗病毒反应中的关键分子。
