HAX1 mediates SARS-CoV-2 spike-triggered unfolded protein response in host cells

文献类型： 外文期刊

第一作者： Zhu, Fang

作者： Zhu, Fang;Yang, Cong;Ren, Jin;Wang, Chengcheng;Hu, Ronggui;Sheng, Xiangpeng;Yang, Fan;Hu, Ronggui;Yang, Fan;Hu, Ronggui;Wang, Xuechen

作者机构：

关键词： ER stress; HAX1; SARS-CoV-2; Spike; unfolded protein response

期刊名称：FEBS JOURNAL （ 影响因子：4.2； 五年影响因子：5.6 ）

ISSN： 1742-464X

年卷期： 2025 年

页码：

收录情况： SCI

摘要： SARS-CoV-2 continues to evolve with enhanced transmissibility, a feature primarily mediated by its spike (S) protein. While expression of the S protein in human cells can induce the accumulation of reactive oxygen species (ROS), the regulatory mechanisms governing this process remain poorly understood. Here, we identify the human protein HCLS1-associated protein X-1 (HAX1) as a key regulator that mitigates SARS-CoV-2S-induced ROS accumulation. A genome-wide screen revealed HAX1 as a binding partner of the SARS-CoV-2S protein in mammalian cells. HAX1 specifically interacts with the S1 subunit of S, and its deficiency effectively abolishes S-induced activation of endoplasmic reticulum (ER) stress responses, including the unfolded protein response (UPR). Notably, HAX1-dependent UPR activation is unique to SARS-CoV-2S and certain variants and is not triggered by other UPR inducers. Loss of HAX1 markedly exacerbates SARS-CoV-2S-induced ROS accumulation and mitochondrial dysfunction. Collectively, our findings uncover a previously unrecognized mechanism by which S modulates host stress responses and establish HAX1 as a host factor involved in SARS-CoV-2-related processes.

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