HAX1 mediates SARS ‐ CoV ‐2 spike‐triggered unfolded protein response in host cells
Fang Zhua, Xiangpeng Shengb✉, Fan Yangc d, Xuechen Wange, Cong Yanga, Jin Rena, Chengcheng Wanga✉, Ronggui Hua c d✉
- aSchool of Medicine Guizhou University Guiyang China
- bState Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute Chinese Academy of Agricultural Sciences Harbin China
- cState Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science University of Chinese Academy of Sciences, Chinese Academy of Sciences Shanghai China
- dThe Second Affiliated Hospital, Liangzhu Laboratory Zhejiang University School of Medicine Hangzhou China
- eShanghai Key Laboratory of Plant Molecular Sciences, College of Life Sciences Shanghai Normal University Shanghai China
- ✉Corresponding author
Papers open inside SciRah from the original publisher or repository; SciRah never hosts them.
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.