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) 是一种干扰素诱导型抗病毒因子，因其能够阻止受感染细胞释放包膜病毒而闻名。然而，其在 I 型干扰素 (IFN) 信号传导中的作用仍不清楚。在这里，我们通过靶向 MAVS 证明 Tetherin 是 RIG-I 样受体 (RLR) 介导的 I 型 IFN 信号传导的负调节因子。 I 型 IFN 诱导 Tetherin 通过泛素依赖性选择性自噬在人体细胞中加速 MAVS 降解。此外，Tetherin 招募 E3 泛素连接酶 MARCH8 催化 MAVS 赖氨酸 7 处的 K27 连接泛素链，作为 NDP52 依赖性自噬降解的识别信号。综上所述，我们的研究结果揭示了 Tetherin-MARCH8-MAVS-NDP52 轴产生的 RLR 信号负反馈环路，并为更好地理解选择性自噬和 I 型 IFN 信号最佳失活之间的串扰提供了见解。