PACT inhibits the replication of SARS‐CoV‐2 through the blockage of GSK‐3β‐N‐nsp3 cascade

Abstract

AbstractThe protein activator of protein kinase R (PKR) (PACT) has been shown to play a crucial role in stimulating the host antiviral response through the activation of PKR, retinoic acid‐inducible gene I, and melanoma differentiation‐associated protein 5. Whether PACT can inhibit viral replication independent of known mechanisms is still unrevealed. In this study, we show that, like many viruses, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) hijacks GSK‐3β to facilitate its replication. GSK‐3β‐induced phosphorylation on N protein increased the interaction between N protein and nsp3. Thus, GSK‐3β‐N‐nsp3 cascade promotes viral replication. Although SARS‐CoV‐2 can sabotage the activation of AKT, the upstream proteins suppressing the activation of GSK‐3β, we found that the host can use PACT, another protein kinase, instead of AKT to decrease the activity of GSK‐3β and the interaction between PACT and GSK‐3β is enhanced upon viral infection. Moreover, PACT inhibited the activity of GSK‐3β independent of its well‐studied double‐stranded RNA binding and PKR activating ability. In summary, this study identified an unknown function of PACT in inhibiting SARS‐CoV‐2 replication through the blockage of GSK‐3β‐N‐nsp3 cascade.