Human Adenoviruses dependent regulation of Human Endogenous Retroviruses expression as a prerequisite for cancer development

Abstract

Human adenoviruses (HAdV) for efficient infection needs to ensure genome decondensation and transcription of viral genes. KAP1 regulates these early stages of infection and is also the main epigenetic factor involved in the repression of human endogenous retroviruses (HERVs). Upon infection in cell lines like A549, H1299, and HepaRG, SUMOylated KAP1 degrades, and phosphorylation at Serine 824, Serine 473, gets altered. Changes in HERV levels are observed after infection. The expression of HERV-K decreases in A549 cells, whereas the expression of HERV-K and HERV-W increases in H1299 cells. No significant changes were observed in HERV levels in HepaRG cells. For the determination of viral protein involved in HERV modulation, different HAdV mutants were used. We identified the early viral proteins E1B-55K and E4orf6 to be important players in the KAP1 modulation and HERV reactivation. On the other hand, we observed a change in HERV levels and pluripotency markers in human Induced Pluripotent Stem cells (hIPSc) after infection. Pax6 levels increase, and Nanog level decreases upon infection. KAP1 knockdown in iPS cells leads to a reduction in Pax6 and Nanog expression, whereas an increase in HERV-E expression. From the IFA studies, we speculated increase in Pax6 levels to be related to PML-NBs, which in turn is modulated by E2A or E4orf3. Our work highlights the role of KAP1 and PTMs in regulating HERVs and pluripotency. This study also highlighted the importance of tissue-specific HERV regulation and how adenovirus could transform cells by regulating these processes.