ALG6 orchestrates coronavirus replication via the endoplasmic reticulum stress-autophagy axis.

Coronaviruses (CoVs) constitute a major global health threat, and their replication is inseparable from host factors. Investigating host-virus interactions is critical for elucidating the CoV life cycle. Here, we identify alpha-1,3-glucosyltransferase (ALG6) as an essential host factor for CoV replication. Mechanistically, its catalytic activity governs transmissible gastroenteritis virus (TGEV) replication, and ALG6 knockout (KO) inhibits viral entry by downregulating the receptor aminopeptidase N (ANPEP). Moreover, our results indicate that ALG6 KO triggers endoplasmic reticulum (ER) stress, resulting in suppressed viral replication. Further investigations demonstrate that ALG6 KO predominantly hinders viral replication by triggering downstream autophagy induced by ER stress. Transmission electron microscopy analysis reveals that ALG6 KO disrupts the formation of double-membrane vesicles (DMVs) during the initial stages of viral replication. In summary, our findings underscore the crucial role of ALG6 in the replication of CoVs, presenting a promising avenue for the development of potential therapeutic strategies against future CoV infections.