Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China.
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China; Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510006, China.
Mol Cell. 2017 Oct 19;68(2):308-322.e4. doi: 10.1016/j.molcel.2017.09.005. Epub 2017 Sep 28.
Tetherin (BST2/CD317) is an interferon-inducible antiviral factor known for its ability to block the release of enveloped viruses from infected cells. Yet its role in type I interferon (IFN) signaling remains poorly defined. Here, we demonstrate that Tetherin is a negative regulator of RIG-I like receptor (RLR)-mediated type I IFN signaling by targeting MAVS. The induction of Tetherin by type I IFN accelerates MAVS degradation via ubiquitin-dependent selective autophagy in human cells. Moreover, Tetherin recruits E3 ubiquitin ligase MARCH8 to catalyze K27-linked ubiquitin chains on MAVS at lysine 7, which serves as a recognition signal for NDP52-dependent autophagic degradation. Taken together, our findings reveal a negative feedback loop of RLR signaling generated by Tetherin-MARCH8-MAVS-NDP52 axis and provide insights into a better understanding of the crosstalk between selective autophagy and optimal deactivation of type I IFN signaling.
tetherin（bst2/cd317）是一种干扰素诱导的抗病毒因子，其能够阻止受感染细胞释放包膜病毒，这一特性使其广为人知。然而， tetherin 在 I 型干扰素（ifn）信号转导中的作用仍未得到明确界定。在这里，我们证明 tetherin 通过靶向 mafs 作为 rig-i 样受体（rlr）介导的 i 型 ifn 信号转导的负调节剂。ifn 的诱导加速了人细胞中通过泛素依赖性选择性自噬的 mafs 降解。此外，tetherin 将 e3 泛素连接酶 march8 募集到 mafs 上的赖氨酸 7 上，催化 mavs 上的 k27 连接泛素链，该赖氨酸 7 是 ndp52 依赖性自噬降解的识别信号。总之，我们的研究结果揭示了 tetherin-march8-mafs-ndp52 轴产生的 rlr 信号的负反馈回路，并为深入了解选择性自噬和 i 型 ifn 信号最佳失活之间的串扰提供了新的见解。
