2025/06/26 by Fang Zhu, Xiangpeng Sheng, Fan Yang +5 · 1 voice
Medicine · Biochemistry, Genetics and Molecular Biology · #Erythrocyte Function and Pathophysiology #Blood disorders and treatments #Diabetes and associated disorders
paper · doi:10.1111/febs.70163
openalex publication_date 2025/06/26 · openalex created_date 2025/06/27 · openalex updated_date 2026/07/22
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.