Human papillomavirus E7 inhibits immune responses in keratinocytes by activating HTRA1‑mediated mitophagy

Persistent infection with human papillomavirus (HPV) can lead to refractory disease. The HPV E7 protein causes persistent viral infection by disrupting the immune balance of keratinocytes; however, its key mechanism is not yet clear. Overexpression of the HPV E7 gene in normal human epidermal keratinocytes can promote mitophagy in the host cells and inhibit the expression of type I interferon (IFN), as previously confirmed by electron microscopy, immunofluorescence and western blot analysis. In the present study, Siha cells with stable knockdown of HPV16 E7 were constructed, and RNA sequencing at the transcription level and isobaric tags for relative and absolute quantitation analysis at the protein level were performed, with the aim of identifying genes related to mitophagy among the differentially expressed genes. Using immunohistochemistry, PCR and western blotting, significant differences were detected in the expression levels of high‑temperature requirement A serine peptidase 1 (HTRA1) between the knockdown and control groups. The results confirmed that HPV E7 could promote the expression of HTRA1. Furthermore, it was demonstrated that the HPV E7 protein interacted with HTRA1 intracellularly to activate the PTEN‑induced kinase 1 (PINK1)/Parkin pathway in keratinocytes, leading to enhanced mitophagy and reduced expression of type I IFN in host cells. In conclusion, HPV E7 could promote the expression of the HTRA1 gene in keratinocytes, thereby activating mitophagy mediated by the PINK1/Parkin pathway. Furthermore, HPV E7 could inhibit the secretion of type I IFN from cells, thus leading to persistent viral infection. These findings provide novel insights into the association between HPV infection and mitophagy, and may elucidate the mechanisms underlying persistent HPV infection.1.