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

Fang Zhu, Xiangpeng Sheng, Fan Yang, Xuechen Wang, Cong Yang, Jin Ren, Chengcheng Wang, Ronggui Hu
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Abstract

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.

HAX1介导宿主细胞中SARS-CoV-2刺突触发的未折叠蛋白反应
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。虽然人类细胞中S蛋白的表达可以诱导活性氧(ROS)的积累,但控制这一过程的调节机制尚不清楚。在这里,我们发现人类蛋白hcls1相关蛋白X-1 (HAX1)是减轻sars - cov - 2s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-2S蛋白的结合伙伴。HAX1特异性地与S的S1亚基相互作用,其缺失有效地消除S诱导的内质网(ER)应激反应的激活,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-2S和某些变体所特有的,不会被其他UPR诱导剂触发。HAX1基因缺失可显著加剧sars - cov - 2s诱导的ROS积累和线粒体功能障碍。总之,我们的研究结果揭示了一个以前未被认识的机制,通过该机制,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。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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