SGK2 induces apoptosis by inhibiting protective autophay via upregulation of mTOR pathway

 Original Paper Link Here.

        HSV stromal keratitis (HSK) is a dangerous disease, with no effective treatment, in the cornea caused by Herpes Simplex Virus 1 (HSV-1) infection that can lead to blindness (1). According to the CDC data, the prevalence of HSV-1 during 2015 to 2016 was 47.8% (2). That's almost half of the population in the US carrying HSV-1! Another study also indicates that the HSV-1 prevalence is 63.5% in adult and 38.0% in general-population children (3). Furthermore, once you get HSV-1, it remains in your body permanently (4). So, what is HSV-1?

        HSV-1 is an enveloped virus with a large, linear double stranded DNA genome contained in an icosahedral capsid (5). There are proteins called the tegument between the caspid and the viral envelope, playing an important role for the viral replication of HSV-1 as they are responsible for the expression of viral gene, delivery of the capsid host cell nucleus, capsid egress (release of the newly synthesized viral capsid from the host nucleus to cytoplasm), and the acquisition of the viral envelope (6). HSV-1 initially attach to the cellular plasma membrane with its glycoprotein B (gB) and gC to host glycosaminoglycans (GAG), located on the host cell surface and extracellular matrix, followed by interaction of gD with several entry receptors (6). HSV-1 starts an initial round of lytic cycle infection in epithelial cells such as orolabial, ocular, or genital epithelial cells, and enter latency in neurons residing in the local peripheral nerve ganglion, which reactivates when host immunity weakens, creating an opportunity for the virus(7).  The structure of HSV-1 is shown in the graph below (6). 

        Here, we discuss a recent paper by Liu, et al. published in Virology Journal in March 2026 that aims for investigating a potential therapy for HSK, given the limited efficacy of current treatments and the increasing risk of drug resistance, and discovered a protein, SGK2, upregulated in the HSV-1 infection in the human corneal epithelial cells (HCEC) and mice corneal tissues. SGK2 is a protein in the SGK (serum and glucocorticoid-regulated kinase) family, which consists of SGK1, 2, and 3. According to Liu, et al, previous researches have unveiled that SGK1 and 3 inhibit autophagy via stimulation of mammalian target of rapamycin (mTOR) pathway, which has an inhibitory effect on autophagy, is establish in the research field. However, the role of SGK2 in this process remain unclear. Liu et al. decided to elucidate this matter, by infecting HCEC and mice cornea with HSV-1 to evaluate the viral replication and apoptosis, and inhibiting SGK2 to observe its effect. 

        They started off with microscopic imaging showing representative images of morphological changes to the HCECs due to HSV-1 infection, as demonstrated in Fig. 1A. Then, an immunoblot, image and quantification shown in Fig. 1B demonstrating the expression of viral protein ICP4, ICP0, and HSV-1-gD (Familiar? It's the glycoprotein that binds viral receptors!), along with the apoptosis-related proteins, Bcl-2 and Bax. From the blot image and the quantification data(Fig. 1B&C), viral protein was only detected on the HSV-1 lane, and Bcl-2, a pro-survival protein, was decreased in the HSV-1 lane, while Bax, a pro-apoptotic protein, was increased. This indicates that the HSV-1 infection in HCECs is pro-apoptotic and can lead to more apoptosis, which was corroborated by flow cytometry and TUNEL assay data in Fig. 1D, E, and F, which are the flow cytometry plot (panel D),  quantification data (E), and TUNEL assay image (F). In panel E, more apoptotic cells was indicated in the chart in HSV-1 infected HCECs, and in the TUNEL assay data, more apoptotic cells were stained (red staining) in HSV-1 infected HCECs. Moreover, they also implemented fluorescein staining imaging of the HSV-1 infected mice cornea and control, as well as a TUNEL assay to evaluate effects on apoptotic in vivo, as demonstrated in panel G, H, and I. The fluorescein staining in panel G is indicating structural disorganization, and the TUNEL assay showing more apoptosis in the HSV-1 infected cornea. Therefore, they concluded that HSV-1 infection promotes apoptosis both in vivo and in vitro.

Figure 1

        Next,  they did a heatmap on differentially expressed gene (DEG) from HSV-1 infection in Fig. 2B, and discovered that SGK2's expression is upregulated in HSV-1 infected HCECs, indicated by the red blocks at the SGK2 row, and relatively down regulated in uninfected HCECs, indicated by the blue row. This indicates that SGK2 is upregulated by the HSV-1 infection, and possibly benefiting the viral replication.

Figure. 2B

        To investigate whether SGK2 is significantly impacting HSV-1 replication, the authors inhibited SGK2 expression by using a chemical inhibitor called GSK650,394 and shRNA silencing SGK2. Effectiveness of both inhibitors was demonstrated in Figure 2, although not shown here. In Fig. 3C (immunoblot) and D (quantification of C), viral protein ICP4, ICP0, and HSV-1 gD was reduced by GSK650,394 treatment, indicating that the inhibition of SGK2 impairs HSV-1 replication. Fig.3 E and F is the cell western assay and immunofluorescence staining that demonstrated the inhibition of SGK2 by GSK650,394 inhibited HSV1-gD in HCECs. Similar effects was also observed in HCECs when treated with shRNA of SGK2. 

        Figure 3

        In Figure 4, they repeated the experiments in Figure 1 with SGK2 inhibition treatment and discovered that the inhibiton of SGK2 resulted in a decrease in apoptosis, indicating that SGK2 is not only responsible for facilitating HSV-1 replication, but also for promoting apoptosis. 

Figure 4

        In Figure 5, the authors demonstrated that HSV-1 infection induced SGK2 inhibits autophagy by stimulating the mTOR pathway by phosphorylation of mTOR and phosphorylation of TSC2 that lead to lower level of TSC2 protein, demonstrated by immunoblot and immunofluorescence image.  TSC2 has an inhibitory effect on mTOR, which is an inhibitory pathway for autophagy. HSV-1 infection causes a higher level of mTOR and a lower level of TSC2, and GSK650,394 reverse the effect, shown in Panel E.

Figure 5

        In Figure 6, the authors further demonstrated that the induction of autophagy by rapamycin (RAPA) inhibits apoptosis, by immunoblotting the autophagy related protein, shown in Panel A and B, and apoptotic related protein Bax and Bcl-2, shown in Panel G and H. In Panel A and B, a higher level of p62, a protein that gets consumed when autophagy takes place, is observed in HSV-1 infected HCECs, and the level dropped following induction of autophagy by RAPA, indicating successful induction of autophagy by RAPA, which was further validated by TEM images of HCECs showing autophagosomes formation and immunofluorescence images of p62. Panel A and B also demonstrated a higher ratio of LC3-II/LC3-I in RAPA treated HCECs, which indicates formation of autophagosomes. 

Figure 6

        In conclusion, Liu et al. demonstrated that HSV-1 induce apoptosis in HCEC and corneal tissue by promoting SGK2 expression, which inhibits autophagy, by phosphorylating TSC2 and mTOR that increases overall mTOR expression, which protects the host cells from apoptosis. This research gives an insight into potential research direction in developing an effective therapy for HSK by targeting SGK2 for inhibition or degradation.

References

1.  

1. Liu, S., Wang, Y., Kong, X., Yan, Y., Wang, Q., Jang, F., & Ye, W. (2026). SGK2 mediates apoptosis in herpes simplex keratitis by suppressing protective autophagy via the mTOR pathway. Virology Journal, 23(1), 109. https://doi.org/10.1186/s12985-026-03131-3

 

2. Products—Data Briefs—Number 304—February 2018. (2019, June 6). https://www.cdc.gov/nchs/products/databriefs/db304.htm

3. Ageeb, R. A., Harfouche, M., Chemaitelly, H., & Abu-Raddad, L. J. (2024). Epidemiology of herpes simplex virus type 1 in the United States: Systematic review, meta-analyses, and meta-regressions. iScience, 27(9), 110652. https://doi.org/10.1016/j.isci.2024.110652

 

4. What Is Herpes Simplex Virus? (n.d.). Cleveland Clinic. Retrieved May 8, 2026, from https://my.clevelandclinic.org/health/diseases/22855-herpes-simplex

 

5. Zhu, S., & Viejo-Borbolla, A. (n.d.). Pathogenesis and virulence of herpes simplex virus. Virulence, 12(1), 2670–2702. https://doi.org/10.1080/21505594.2021.1982373

 

6. Loret, S., Guay, G., & Lippé, R. (2008). Comprehensive Characterization of Extracellular    Herpes Simplex Virus Type 1 Virions. Journal of Virology, 82(17), 8605–8618. https://doi.org/10.1128/JVI.00904-08