SARS-CoV-2-Induced Phosphorylation of HSPA9 at Ser627: Potential Implications for Mitochondrial Function, Cell Cycle Regulation, and Immune Evasion

Abstract

Heat shock proteins (HSPs), particularly those in the HSP70 family, play essential roles in maintaining cellular homeostasis and orchestrating stress responses, including those triggered by viral infections. Based on data mining of published datasets and experimental characterization, this study identified HSPA9 phosphorylation at serine 627 (S627) as a potential regulatory site associated with SARS-CoV-2 infection. Our findings demonstrate that phospho-S627 HSPA9 enhances mitochondrial function and mass, potentially meeting the elevated energy demands of viral replication. Concurrently, phosphorylation at S627 suppresses host cell proliferation, potentially delaying immune activation and facilitating viral spread. Moreover, phosphorylation at both the S627 and S378 sites markedly reduces the expression of the proinflammatory cytokines IL-6 and IL-8, which may further weaken the immune response during SARS-CoV-2 infection. These data suggest that SARS-CoV-2 may exploit HSPA9 phosphorylation to bolster its replication and evade host defenses. Notably, MAPKAPK2 has emerged as a latent kinase that regulates this phosphorylation, making it a promising therapeutic target for the treatment of these conditions. Overall, our results shed light on a novel mechanism of SARS-CoV-2 pathogenesis, suggesting that HSPA9 phosphorylation may be a potential therapeutic target.