Hepatitis C virus (HCV) entry into hepatocytes is a complex process involving multiple cellular factors, including the scavenger receptor class B type 1 (SR-B1), the tetraspanin CD81, and the tight junction (TJ) proteins claudin-1 (CLDN1) and occludin (OCLN). Here, researchers identified tumor-associated calcium signal transducer 2 (TACSTD2) as one of the most downregulated genes in primary hepatocellular carcinoma (HCC) tissues. It is a host factor that interacts with CLDN1 and OCLN and regulates their cellular localization. TACSTD2 gene silencing disrupts the typical linear distribution of CLDN1 and OCLN along the cell membrane in both HCC cells and primary human hepatocytes, consistent with the in vivo pattern observed in primary HCC tissues. Mechanistic studies revealed that TACSTD2 is involved in the phosphorylation of CLDN1 and OCLN, which is required for their proper cellular localization. Silencing TACSTD2 significantly inhibited HCV infection and produced a genotype-wide effect at the level of viral entry. The study revealed that TACSTD2 is a novel regulator of two major HCV entry factors, CLDN1 and OCLN, which are significantly downregulated in malignant hepatocytes. These results provide new insights into the complex process of HCV invasion of hepatocytes and may aid in the development of more efficient cell systems for HCV proliferation in vitro.
Here, researchers evaluated whether HCV infection is more efficient in TACSTD2-overexpressing Huh7.5 cells by comparing infection with all HCV genotypes in TACSTD2-overexpressing Huh7.5 cells compared to parental Huh7.5 cells. The data showed that HCV infection rates were consistently higher in TACSTD2-overexpressing cells, further confirming the role of TACSTD2 in HCV infection. Differences were more pronounced 24 hours after infection and were statistically significant for HCV genotypes 1a, 1b, 3a, 6a, and 7a, but not for HCV genotypes 2b, 4a, and 5a. In genotypes 1a, 6a, and 7a, HCV infection rates were significantly higher at both 24 and 48 hours post-infection (Figure 1). Finally, researchers evaluated whether HCV infection affects TACSTD2 expression levels during HCV infection. They found that HCV infection did not significantly affect TACSTD2 expression.
Figure 1. HCV infection in parental and TACSTD2 overexpressing Huh7.5 cells. (Sekhar V, et al., 2018)