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Infection of the upper aero-digestive tract with low-risk and high-risk human papillomaviruses is the cause of recurrent respiratory papillomatosis and a subset of head and neck cancers, respectively. E6 protein is considered one of the oncoproteins encoded by high-risk HPVs, due to its ability to degrade tumor suppressor p53, activate telomerase, avoid apoptosis and other functions that contribute to carcinogenesis. Most of the functions of high-risk E6 proteins act through interaction with host cellular proteins, while little is known about the cellular interacting partners to low-risk E6 proteins. Here we used GST-pulldown coupled with mass spectrometry to identify potential cellular host proteins to E6 proteins from low-risk types 6 and 11 as well as high-risk type 16. We have identified 40 cellular proteins in complex with GST-6E6, 93 proteins with GST-11E6, and 179 proteins with GST-16E6. Among these bound proteins, we further confirmed SAMD9 as a novel interaction partner to low-risk HPV-11 E6 protein by using co-immunoprecipitation, proximity ligation assay, and confocal immunofluorescence staining. SAMD9 is a host restriction factor for myxoma virus and vaccinia virus. We hypothesize that SAMD9 may have an anti-viral effect against HPV-11, which is still to be determined as we need to establish an efficient in vitro HPV-11 replication model. Due to the possibility that HPVs may maintain their genome in the infected host cells in a stem cell-like state to establish persistent infection, which can give rise to benign and malignant cancers, we have also investigated the effects of E6 proteins from a low-risk type HPV-6 and a high-risk type HPV-16 on stem cell-like properties in keratinocytes expressing these proteins. Increased tumor sphere number, ALDH enzyme activity, and elevated stem cell marker Oct4 expression were observed in HPV-16 E6- expressing cells, when compared to those of low-risk HPV-6 E6-expressing cells and control cells. Additionally, a significant increase of interleukin-6 (IL-6) expression was observed in HPV-16 E6-expressing cells. Neutralizing IL-6 can inhibit the Oct4 expression induced by HPV-16 E6 protein. Our study suggests that high-risk HPV-16 E6 upregulates IL-6 expression to promote stem cell-like properties.



human papillomaviruses, E6 protein