TMEM2 inhibits hepatitis B virus infection in HepG2 and HepG2.2.15 cells by activating the JAK–STAT signaling pathway

Abstract

We have previously observed the downregulation of TMEM2 in the liver tissue of patients with chronic hepatitis B virus (HBV) infection and in HepG2.2.15 cells with HBV genomic DNA. In the present study, we investigated the role and mechanism of TMEM2 in HepG2 and HepG2.2.15 during HBV infection HepG2 and HepG2.2.15. HepG2 shTMEM2 cells with stable TMEM2 knockdown and HepG2 TMEM2 and HepG2.2.15 TMEM2 cells with stable TMEM2 overexpression were established using lentivirus vectors. We observed reduced expression of TMEM2 in HBV-infected liver tissues and HepG2.2.15 cells. HBsAg, HBcAg, HBV DNA, and HBV cccDNA levels were significantly increased in HepG2 shTMEM2 cells but decreased in HepG2 TMEM2 and HepG2.2.15 TMEM2 cells compared with naive HepG2 cells. On the basis of the western blotting results, the JAK–STAT signaling pathway was inhibited in HepG2 shTMEM2 cells but activated in HepG2 TMEM2 and HepG2.2.15 TMEM2 cells. In addition, reduced and increased expression of the antiviral proteins MxA and OAS1 was observed in TMEM2-silenced cells (HepG2 shTMEM2 cells) and TMEM2-overexpressing cells (HepG2 TMEM2 and HepG2.2.15 TMEM2 cells), respectively. The expression of Interferon regulatory factor 9 (IRF9) was not affected by TMEM2. However, we found that overexpression and knockdown of TMEM2, respectively, promoted and inhibited importation of IRF9 into nuclei. The luciferase reporter assay showed that IRF9 nuclear translocation affected interferon-stimulated response element activities. In addition, the inhibitory effects of TMEM2 on HBV infection in HepG2 shTMEM2 cells was significantly enhanced by pre-treatment with interferon but significantly inhibited in HepG2.2.15 TMEM2 cells by pre-treatment with JAK1 inhibitor. TMEM2 inhibits HBV infection in HepG2 and HepG2.2.15 by activating the JAK–STAT signaling pathway.

LncRNA expression profiles in HBV‐transformed human hepatocellular carcinoma cells treated with a novel inhibitor of human La protein

“…The top ten enriched pathways were the Jak‐STAT signalling pathway, the p53 signalling pathway, apoptosis and the role of mitochondria in apoptotic signalling (Figure B). All of these pathways are closely associated with HBV infection or cell apoptosis. It appears that upon treatment with H11, the differentially expressed lncRNAs were enriched in apoptotic‐related pathways resulting in suppression of the replication and spread of HBV.…”

“…Pathway analysis of lncRNAs identified the Jak‐STAT signalling pathway, the p53 signalling pathway, apoptosis and the cytochrome c‐mediated apoptotic response. It has been demonstrated that repression of Jak‐STAT signalling is beneficial to HBV replication …”

Anti-viral role of toll like receptor 4 in hepatitis B virus infection: An in vitro study

“…Though, HepG2.2.15 carrying HBV genome is the only cell line used for this study, but this is an extremely relevant model and sufficient work has been done on host-virus interaction[26,32,33] . However, we plan to investigate our work in other relevant cell lines and primary human hepatocytes in future.…”

The Role of Interferon-Inducible Transmembrane Proteins in Virus Infection

“…In addition, IFITM3 could inhibit ZIKV-induced cell death [6]. Another IFITMs superfamily member TMEM2 has been found to inhibit HBV infection by activating the Jak/STAT signaling pathway [7]. Notably, these restricted viruses were all encapsulated, containing the ssRNA genome, and were reported to enter cells by membrane fusion after endocytosis.…”