Sec62 restricts ER-replicating positive-strand RNA virus infections via UPR-dependent ER-phagy.

Positive-strand RNA [(+)RNA] viruses induce endomembrane remodeling to form viral replication organelles (VROs), which disrupt organelle homeostasis. How hosts restore organelle homeostasis and how these responses influence viral replication remain elusive. Using beet black scorch virus (BBSV), a (+)RNA virus that replicates on the endoplasmic-reticulum (ER) and induces severe deformation of ER membranes, as a model in Nicotiana benthamiana, we demonstrated that BBSV induces ER-phagy, primarily mediated by its auxiliary replication protein p23. p23 interacts with the ER-phagy receptor NbSec62, with phenylalanine at position 48 being critical for this interaction and ER-phagy induction. Upon BBSV infection, the unfolded protein response (UPR) is triggered to promote viral replication. However, the activation of the UPR also induces NbSec62-mediated ER-phagy to suppress BBSV replication. Furthermore, NbSec62 restricts other ER-replicating (+)RNA viruses, including tobacco mosaic virus and turnip mosaic virus. Our findings reveal NbSec62 as a restriction factor that interacts with BBSV VROs to regulate the balance of viral replication and ER homeostasis, providing insights into the UPR-ER-phagy signaling network in virus-host interactions.