The <scp>SARS</scp> ‐ <scp>CoV</scp> ‐2 spike protein interacts with <scp>HAX1</scp> to modulate cellular stress responses through activation of the <scp>UPR</scp>

During cell infection, viruses maintain the lifespan of host cells by preserving key functions of cellular organelles such as the endoplasmic reticulum (ER) and mitochondria to guarantee protein secretion and energy production. The host secretory pathway is rapidly hijacked to produce viral proteins and reconstitute viral particles for further viral dissemination. However, secreted protein synthesis and proper folding are tightly regulated in the host ER to maintain homeostasis, otherwise this organelle is subjected to ER stress that triggers an adaptive response named the unfolded protein response (UPR). The UPR first aims at restoring ER function by producing enzymes to correct or eliminate misfolded proteins. If ER stress remains unresolved, the UPR triggers cell death. In the work published by Zhu et al. in this issue of The FEBS Journal, the authors explore a previously undescribed molecular hijacking function of SARS-CoV-2 to limit host cell death. Indeed, the viral spike protein directly interacts with the host HAX1 molecule to promote UPR activation, limiting the production of deleterious reactive oxygen species and mitochondrial dysfunction to maintain host cell survival.