MmuPV1 and HPV E6 Elevate Nuclear Accumulation of IKK? to Impair NF-κB Signaling to Promote Persistent Infection

Abstract

The mouse papillomavirus (MmuPV1) E6 oncoprotein is essential for persistent infection and cancer development. Previous studies identified amino acid R130 of MmuPV1 E6 as critical for its interaction with the tumor suppressor MAML1. Mutation of this residue (R130A) disrupts MAML1 binding and prevents disease development in mice. In this study, we demonstrate that MmuPV1 E6 also disrupts NF-{kappa}B signaling through interactions with proteins in the I{kappa}B kinase (IKK) complex. Specifically, the MmuPV1 E6R130A mutant is defective in binding IKK complex proteins and fails to impair NF-{kappa}B signaling in mouse keratinocytes, suggesting that these interactions are necessary for E6-mediated disruption of this pathway. Furthermore, MmuPV1 E6 expression is associated with increased nuclear localization of IKK?, whereas cells expressing the E6R130A mutant exhibit no such increase. These findings suggest that E6-mediated nuclear localization of IKK? depends on its interaction with IKK complex proteins. Importantly, we demonstrate that the human papillomavirus HPV16 E6 oncoprotein similarly impairs NF-{kappa}B signaling and increases nuclear IKK? localization in human keratinocytes, suggesting a shared mechanism between mouse and human papillomaviruses. Additionally, analysis of previously published RNA sequencing data reveals that MmuPV1 E6 induces several transcriptional changes associated with increased nuclear IKK?. Together, these findings demonstrate that both MmuPV1 and HPV16 E6 disrupt NF-{kappa}B signaling in association with increased nuclear IKK? localization. This study provides the first evidence of an E6 oncoprotein interacting with and changing subcellular localization of IKK? to disrupt cellular homeostasis.