The effect of HSV infection on cellular transcription factors

Infection with herpes simplex virus (HSV) suppresses most cellular gene expression rapidly in the early stage of virus infection. However, this virus also increases gene expression from a few cellular genes such as those encoding heat shock proteins. It is not clear how such effects occur. Alu repeats were induced at the transcriptional level by the action of HSV immediate early (IE) protein ICP27. This effect was mediated through increasing the activity of transcription factor IIIC (TFIIIC) which is the limiting factor for RNA polymerase III (po1III) transcription. This increased activity of TFIIIC appeared to occur by increasing its abundance. Also, other viral transactivators such as adenovirus (Ad) E1A protein, pseudorabies virus (PRV) immediate- early protein, and human immunodeficiency virus (HIV) Tat protein showed the same effect on the expression of Alu repeats to that seen in HSV infection. On the other hand, HSV also produced profound effects on the RNA polymerase II transcription system. HSV increased the activity of a few cellular transcription factors such as AP-1 and NFkB. In contrast, no increase in the activity of several other transcription factors such as Oct-1, Sp1, or ATF was observed. The up-regulation of AP-1 activity appeared to occur through increasing the concentration of c-Jun and possibly c-Fos probably at the transcriptional level by the action of the HSV IE protein ICPO. The significance of the induced pol III gene expression during infection with various viruses is discussed. Also, it is suggested these HSV-induced cellular proto-oncogenes play a role in the regulation of viral and cellular gene expression during lytic infection, and particularly during the processes of cell transformation and herpes virus latency

Hepatitis B virus X protein stimulates cell growth by downregulating p16 levels via PA28γ-mediated proteasomal degradation

Proteasomal activator 28 gamma (PA28γ), an essential constituent of the 20S proteasome responsible for ubiquitin-independent degradation of target proteins, is frequently overexpressed in hepatocellular carcinoma. Recently, we have reported that hepatitis B virus (HBV) X protein (HBx) activates PA28γ expression in human hepatocytes via upregulation of p53 levels; however, its role in HBV tumorigenesis remains unknown. Here, we found that HBx-activated PA28γ downregulates p16 levels via ubiquitin-independent proteasomal degradation. As a result, HBx activated the Rb-E2F pathway and stimulated G1/S cell cycle progression, resulting in an increase in cell proliferation. The potential of HBx to induce these effects was reproduced in a 1.2-mer HBV replicon and in in vitro HBV infection systems and was almost completely abolished by either PA28γ knockdown or p16 overexpression, demonstrating the critical role of the PA28γ-mediated p16 degradation in HBV tumorigenesis.</jats:p

Hydrogen Peroxide Inhibits Hepatitis C Virus Replication by Downregulating Hepatitis C Virus Core Levels through E6-Associated Protein-Mediated Proteasomal Degradation

Hepatitis C virus (HCV) is constantly exposed to considerable oxidative stress, characterized by elevated levels of reactive oxygen species, including hydrogen peroxide (H2O2), during acute and chronic infection in the hepatocytes of patients. However, the effect of oxidative stress on HCV replication is largely unknown. In the present study, we demonstrated that H2O2 downregulated HCV Core levels to inhibit HCV replication. For this purpose, H2O2 upregulated p53 levels, resulting in the downregulation of both the protein and enzyme activity levels of DNA methyltransferase 1 (DNMT1), DNMT3a, and DNMT3b, and activated the expression of E6-associated protein (E6AP) through promoter hypomethylation in the presence of HCV Core. E6AP, an E3 ligase, induced the ubiquitin-dependent proteasomal degradation of HCV Core in a p53-dependent manner. The inhibitory effect of H2O2 on HCV replication was almost completely nullified either by treatment with a representative antioxidant, N-acetyl-L-cysteine, or by knockdown of p53 or E6AP using a specific short hairpin RNA, confirming the roles of p53 and E6AP in the inhibition of HCV replication by H2O2. This study provides insights into the mechanisms that regulate HCV replication under conditions of oxidative stress in patients

All-trans Retinoic Acid Inhibits Hepatitis B Virus Replication by Downregulating HBx Levels via Siah-1-Mediated Proteasomal Degradation

All-trans retinoic acid (ATRA), the most biologically active metabolite of vitamin A, is known to abolish the potential of HBx to downregulate the levels of p14, p16, and p21 and to stimulate cell growth during hepatitis B virus (HBV) infection, contributing to its chemopreventive and therapeutic effects against HBV-associated hepatocellular carcinoma. Here, we demonstrated that ATRA antagonizes HBx to inhibit HBV replication. For this effect, ATRA individually or in combination with HBx upregulated p53 levels, resulting in upregulation of seven in absentia homolog 1 (Siah-1) levels. Siah-1, an E3 ligase, induces ubiquitination and proteasomal degradation of HBx in the presence of ATRA. The ability of ATRA to induce Siah-1-mediated HBx degradation and the subsequent inhibition of HBV replication was proven in an in vitro HBV replication model. The effects of ATRA became invalid when either p53 or Siah-1 was knocked down by a specific shRNA, providing direct evidence for the role of p53 and Siah-1 in the negative regulation of HBV replication by ATRA