White Elizabeth A, Münger Karl, Howley Peter M
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA
Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USA.
mBio. 2016 Sep 20;7(5):e01530-16. doi: 10.1128/mBio.01530-16.
The major transformation activity of the high-risk human papillomaviruses (HPV) is associated with the E7 oncoprotein. The interaction of HPV E7 with retinoblastoma family proteins is important for several E7 activities; however, this interaction does not fully account for the high-risk E7-specific cellular immortalization and transformation activities. We have determined that the cellular non-receptor protein tyrosine phosphatase PTPN14 interacts with HPV E7 from many genus alpha and beta HPV types. We find that high-risk genus alpha HPV E7, but not low-risk genus alpha or beta HPV E7, is necessary and sufficient to reduce the steady-state level of PTPN14 in cells. High-risk E7 proteins target PTPN14 for proteasome-mediated degradation, which requires the ubiquitin ligase UBR4, and PTPN14 is degraded by the proteasome in HPV-positive cervical cancer cell lines. Residues in the C terminus of E7 interact with the C-terminal phosphatase domain of PTPN14, and interference with the E7-PTPN14 interaction restores PTPN14 levels in cells. Finally, PTPN14 degradation correlates with the retinoblastoma-independent transforming activity of high-risk HPV E7.
High-risk human papillomaviruses (HPV) are the cause of cervical cancer, some other anogenital cancers, and a growing fraction of oropharyngeal carcinomas. The high-risk HPV E6 and E7 oncoproteins enable these viruses to cause cancer, and the mechanistic basis of their carcinogenic activity has been the subject of intense study. The high-risk E7 oncoprotein is especially important in the immortalization and transformation of human cells, which makes it a central component of HPV-associated cancer development. E7 oncoproteins interact with retinoblastoma family proteins, but for several decades, it has been recognized that high-risk HPV E7 oncoproteins have additional cancer-associated activities. We have determined that high-risk E7 proteins target the proteolysis of the cellular protein tyrosine phosphatase PTPN14 and find that this activity is correlated with the retinoblastoma-independent transforming activity of E7.
高危型人乳头瘤病毒（HPV）的主要转化活性与E7癌蛋白相关。HPV E7与视网膜母细胞瘤家族蛋白的相互作用对E7的多种活性很重要；然而，这种相互作用并不能完全解释高危型E7特异性的细胞永生化和转化活性。我们已经确定细胞非受体蛋白酪氨酸磷酸酶PTPN14与许多α属和β属HPV类型的HPV E7相互作用。我们发现高危型α属HPV E7，而非低危型α属或β属HPV E7，对于降低细胞中PTPN14的稳态水平是必要且充分的。高危型E7蛋白将PTPN14靶向蛋白酶体介导的降解，这需要泛素连接酶UBR4，并且PTPN14在HPV阳性的宫颈癌细胞系中被蛋白酶体降解。E7 C末端的残基与PTPN14的C末端磷酸酶结构域相互作用，干扰E7 - PTPN14相互作用可恢复细胞中PTPN14的水平。最后，PTPN14降解与高危型HPV E7的不依赖视网膜母细胞瘤的转化活性相关。
高危型人乳头瘤病毒（HPV）是宫颈癌、其他一些肛门生殖器癌以及越来越多的口咽癌的病因。高危型HPV E6和E7癌蛋白使这些病毒能够致癌，其致癌活性的机制基础一直是深入研究的主题。高危型E7癌蛋白在人类细胞的永生化和转化中尤为重要，这使其成为HPV相关癌症发展的核心组成部分。E7癌蛋白与视网膜母细胞瘤家族蛋白相互作用，但几十年来，人们已经认识到高危型HPV E7癌蛋白具有其他与癌症相关的活性。我们已经确定高危型E7蛋白靶向细胞蛋白酪氨酸磷酸酶PTPN14的蛋白水解，并发现这种活性与E7的不依赖视网膜母细胞瘤的转化活性相关。
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