PTPN14 degradation by high-risk human papillomavirus E7 limits keratinocyte differentiation and contributes to HPV-mediated oncogenesis
PTPN14 degradation by high-risk human papillomavirus E7 limits keratinocyte differentiation and contributes to HPV-mediated oncogenesis
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高危人乳头瘤病毒 E7 对 PTPN14 的降解限制了角质形成细胞的分化，并促进了 HPV 介导的肿瘤发生
DOI：
10.1073/pnas.1819534116
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发表时间：
2019-04-02
影响因子：
11.1
通讯作者：
White, Elizabeth A.
中科院分区：
文献类型：
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作者：
Hatterschide, Joshua;Bohidar, Amelia E.;White, Elizabeth A.
高危人乳头瘤病毒（HPV） E7蛋白通过使宿主细胞蛋白失活，使HPV感染的细胞发生致癌转化。高风险而非低风险的HPV E7靶向PTPN14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。使用HPV16 E7变体可以灭活视网膜母细胞瘤肿瘤抑制因子（RB1），但不能降解PTPN14，我们发现高危HPV E7介导的PTPN14降解会损害角化细胞分化。原代人角质形成细胞中PTPN14的缺失降低了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PTPN14缺失都促进了脱离底物后角质细胞的存活。PTPN14降解有助于高危HPV E6/ e7介导的原发性角化细胞的永化，HPV+而非HPV-癌表现出与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的分化，并提出这有助于不依赖于RB1失活的高危HPV e7介导的致癌活性。
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.