Zhu Fang, Sheng Xiangpeng, Yang Fan, Wang Xuechen, Yang Cong, Ren Jin, Wang Chengcheng, Hu Ronggui
School of Medicine, Guizhou University, Guiyang, China.
State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
FEBS J. 2025 Jun 26. doi: 10.1111/febs.70163.
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.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）继续进化，其传播性增强，这一特征主要由其刺突（S）蛋白介导。虽然S蛋白在人类细胞中的表达可诱导活性氧（ROS）积累，但调控这一过程的机制仍知之甚少。在此，我们确定人类蛋白HCLS1相关蛋白X-1（HAX1）是减轻SARS-CoV-2 S诱导的ROS积累的关键调节因子。全基因组筛选显示HAX1是哺乳动物细胞中SARS-CoV-2 S蛋白的结合伴侣。HAX1特异性地与S的S1亚基相互作用，其缺失有效地消除了S诱导的内质网（ER）应激反应激活，包括未折叠蛋白反应（UPR）。值得注意的是，HAX1依赖的UPR激活是SARS-CoV-2 S和某些变体所特有的，不会由其他UPR诱导剂触发。HAX1的缺失显著加剧了SARS-CoV-2 S诱导的ROS积累和线粒体功能障碍。总体而言，我们的研究结果揭示了一种以前未被认识的机制，即S调节宿主应激反应，并确定HAX1是参与SARS-CoV-2相关过程的宿主因子。
