Department of Otorhinolaryngology: Head and Neck Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111.
Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):7033-7042. doi: 10.1073/pnas.1819534116. Epub 2019 Mar 20.
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 from primary human keratinocytes decreased keratinocyte differentiation gene expression. Related to oncogenic transformation, both HPV16 E7-mediated PTPN14 degradation and 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.
高危型人乳头瘤病毒（HPV）E7 蛋白通过使宿主细胞蛋白失活来实现 HPV 感染细胞的致癌转化。高危型而非低危型 HPV E7 靶向 PTPN14 进行蛋白水解降解，提示 PTPN14 降解可能与其致癌活性有关。HPV 感染人角质形成细胞，但 PTPN14 在角质形成细胞中的作用以及 PTPN14 降解的后果尚不清楚。我们使用一种能够使视网膜母细胞瘤肿瘤抑制因子（RB1）失活但不能降解 PTPN14 的 HPV16 E7 变体，发现高危型 HPV E7 介导的 PTPN14 降解会损害角质形成细胞分化。从原代人角质形成细胞中删除 会降低角质形成细胞分化基因的表达。与致癌转化相关，HPV16 E7 介导的 PTPN14 降解和 缺失均促进了角质形成细胞从基质上脱落后的存活。PTPN14 降解有助于高危型 HPV E6/E7 对原代角质形成细胞的永生化和 HPV 的转化，而不是 HPV 癌症表现出与 PTPN14 失活一致的基因表达特征。我们发现 PTPN14 降解会损害角质形成细胞分化，并提出这有助于高危型 HPV E7 介导的致癌活性，而不依赖于 RB1 失活。
