Coronavirus Nucleocapsid Proteins Hijack Host Protein Kinase A Catalytic Subunit α into Nucleus to Evade from STAT1 Signaling
Xu, J.; Xiao, Y.; Lu, W.; Song, Z.; Zhou, L.; Gao, Q.; Xu, X.; Shan, Y.; Fang, W.; Zhao, L.; Li, X.
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The role of the cAMP/PKA pathway in antiviral innate immunity, including during coronavirus infections, remains unclear. We discovered coronavirus N proteins initiate cAMP-ADCY10-PKA cascade. Cytoplasmic PKA activates STAT1 independently of canonical JAK/TYR2 signaling. Coronavirus N proteins, via a conserved arginine (e.g., PEDV R58, SARS-CoV-2 R92), directly bind and sequester PKA C into the nucleus to evade STAT1 activation. Using PEDV as a model, mutant viruses with NmutNLS and NR58A were generated. Wildtype PEDV infection suppressed STAT1 activation in cells expressing PKA C/PKA CS339A deficient in STAT1 phosphorylation. However, in rXS0101mutNLS- or rXS0101R58A-infected cells, only PKA CS339A expression inhibited STAT1 activation. Downregulation of STAT1 activation is accompanied with increased viral replication. This study first elaborates that PKA C activates STAT1 in the cytoplasm of infected cells distinctly from canonical JAK/STAT1 signaling, while coronaviruses evade this antiviral response by sequestering PKA C into the nucleus via direct N protein interaction.
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