SGK2 mediates apoptosis in herpes simplex keratitis by suppressing protective autophagy via the mTOR pathway

Herpes simplex virus type 1 (HSV-1) is a common human pathogen of herpes simplex keratitis (HSK), one of the leading causes of infectious blindness worldwide. Antiviral therapies remain limited by their dependence on active viral replication and rising drug resistance. This study aimed to explore the role of serum and glucocorticoid-regulated kinase 2 (SGK2) in regulating apoptosis and autophagy in HSV-1 infected corneal epithelial cells (CECs).

Human corneal epithelial cells (HCECs) and mouse corneas were infected with HSV-1 to evaluate HSV-1 replication and apoptosis. RNA sequencing of uninfected and HSV-1 infected HCECs was performed to identify differentially expressed genes associated with infection. SGK2 expression was assessed in vitro and in vivo via RT-qPCR, western blot, and immunofluorescence staining. SGK2 was pharmacologically inhibited with GSK 650,394, and genetically knocked down using shRNA, and autophagy was activated with rapamycin (RAPA). The regulatory roles of the SGK2/TSC2/mTOR pathway in apoptosis and autophagy were investigated using western blot, immunofluorescence staining, flow cytometry, and in cell western assay.

HSV-1 infection significantly increased apoptosis and SGK2 expression in HCECs and mice CECs. Moreover, upregulation of SGK2 activated the mTOR pathway by promoting TSC2 protein degradation, thereby suppressing protective autophagy, enhancing apoptosis, and promoting HSV-1 replication. Treatment with the SGK2 inhibitor GSK 650,394 or shRNA-mediated SGK2 knockdown markedly attenuated these effects. Furthermore, the activation of autophagy with RAPA effectively suppressed HSV-1 induced apoptosis.

These findings indicate that HSV-1 modulates host autophagy via the SGK2/TSC2/mTOR signaling axis to induce apoptosis in CECs, suggesting SGK2 as a potential molecular target for HSV-1 therapy.