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

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.