PTPN14 degradation by high-risk human papillomavirus E7 limits keratinocyte differentiation and contributes to HPV-mediated oncogenesis

Menée in vitro, cette étude met en évidence un mécanisme par lequel la protéine E7 des papillomavirus humains à haut risque, en favorisant la dégradation de la tyrosine phosphatase PTPN14, limite la différenciation des kératinocytes et participe à la carcinogenèse

Résumé en anglais

Human papillomaviruses (HPV) uncouple proliferation from differentiation to enable virus replication in epithelial cells. HPV E7 proteins are well established to promote proliferation by binding to and inactivating retinoblastoma family proteins and other cell cycle inhibitors. However, mechanisms by which high-risk HPV oncoproteins inhibit differentiation have not been defined. This paper identifies a mechanism by which high-risk HPV E7 inhibit keratinocyte differentiation. The inhibition of differentiation requires degradation of the cellular protein PTPN14 by high-risk HPV E7, and this degradation is related to the ability of high-risk HPV oncoproteins to immortalize keratinocytes and to cause cancer.High-risk human papillomavirus (HPV) E7 proteins enable oncogenic transformation of HPV-infected cells by inactivating host cellular proteins. High-risk but not low-risk HPV E7 target PTPN14 for proteolytic degradation, suggesting that PTPN14 degradation may be related to their oncogenic activity. HPV infects human keratinocytes but the role of PTPN14 in keratinocytes and the consequences of PTPN14 degradation are unknown. Using an HPV16 E7 variant that can inactivate retinoblastoma tumor suppressor (RB1) but cannot degrade PTPN14, we found that high-risk HPV E7-mediated PTPN14 degradation impairs keratinocyte differentiation. Deletion of PTPN14 from primary human keratinocytes decreased keratinocyte differentiation gene expression. Related to oncogenic transformation, both HPV16 E7-mediated PTPN14 degradation and PTPN14 deletion promoted keratinocyte survival following detachment from a substrate. PTPN14 degradation contributed to high-risk HPV E6/E7-mediated immortalization of primary keratinocytes and HPV+ but not HPV− cancers exhibit a gene-expression signature consistent with PTPN14 inactivation. We find that PTPN14 degradation impairs keratinocyte differentiation and propose that this contributes to high-risk HPV E7-mediated oncogenic activity independent of RB1 inactivation.