High-Risk Human Papillomavirus E7 Proteins Target PTPN14 for Degradation
ABSTRACT 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-...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2016-11-01
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| Series: | mBio |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.01530-16 |
| _version_ | 1828955967202525184 |
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| author | Elizabeth A. White Karl Münger Peter M. Howley |
| author_facet | Elizabeth A. White Karl Münger Peter M. Howley |
| author_sort | Elizabeth A. White |
| collection | DOAJ |
| description | ABSTRACT 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. IMPORTANCE 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. |
| first_indexed | 2024-12-14T08:02:28Z |
| format | Article |
| id | doaj.art-48b42be47f234822b503ae440d22e202 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-14T08:02:28Z |
| publishDate | 2016-11-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-48b42be47f234822b503ae440d22e2022022-12-21T23:10:19ZengAmerican Society for MicrobiologymBio2150-75112016-11-017510.1128/mBio.01530-16High-Risk Human Papillomavirus E7 Proteins Target PTPN14 for DegradationElizabeth A. White0Karl Münger1Peter M. Howley2Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USADepartment of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USADepartment of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USAABSTRACT 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. IMPORTANCE 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.https://journals.asm.org/doi/10.1128/mBio.01530-16 |
| spellingShingle | Elizabeth A. White Karl Münger Peter M. Howley High-Risk Human Papillomavirus E7 Proteins Target PTPN14 for Degradation mBio |
| title | High-Risk Human Papillomavirus E7 Proteins Target PTPN14 for Degradation |
| title_full | High-Risk Human Papillomavirus E7 Proteins Target PTPN14 for Degradation |
| title_fullStr | High-Risk Human Papillomavirus E7 Proteins Target PTPN14 for Degradation |
| title_full_unstemmed | High-Risk Human Papillomavirus E7 Proteins Target PTPN14 for Degradation |
| title_short | High-Risk Human Papillomavirus E7 Proteins Target PTPN14 for Degradation |
| title_sort | high risk human papillomavirus e7 proteins target ptpn14 for degradation |
| url | https://journals.asm.org/doi/10.1128/mBio.01530-16 |
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