Glucose-regulated protein 94 (Grp94/gp96) in viral pathogenesis: Insights into its role and therapeutic potentials

Glucose-regulated protein 94 (Grp94/gp96) is endoplasmic reticulum (ER) resident form of the 90 kDa heat shock protein 90 (Hsp90) that is responsible for folding, maturation and stabilization of more than 400 client proteins. Grp94 has been implicated for various diseases including metastatic cancer, primary open-angle glaucoma, and infectious diseases. In fact, Grp94 plays critical roles in different stages of viral infection cycle. It chaperones receptor proteins and viral glycoproteins that are necessary for viral entry and replication. Beyond its role in protein homeostasis, Grp94 modulates host cellular processes such as apoptosis and immune responses, which are often exploited by viruses to sustain infection. This work provides an overview of the roles of Grp94 in viral pathogenesis across various viruses and its involvement in immune modulation with the development of Grp94-selective inhibitors and their potential as anti-viral therapeutics.