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-...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Elizabeth A. White, Karl Münger, Peter M. Howley
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/48b42be47f234822b503ae440d22e202
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:48b42be47f234822b503ae440d22e202
record_format	dspace
spelling	oai:doaj.org-article:48b42be47f234822b503ae440d22e2022021-11-15T15:50:14ZHigh-Risk Human Papillomavirus E7 Proteins Target PTPN14 for Degradation10.1128/mBio.01530-162150-7511https://doaj.org/article/48b42be47f234822b503ae440d22e2022016-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01530-16https://doaj.org/toc/2150-7511ABSTRACT 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.Elizabeth A. WhiteKarl MüngerPeter M. HowleyAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 5 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Elizabeth A. White Karl Münger Peter M. Howley High-Risk Human Papillomavirus E7 Proteins Target PTPN14 for Degradation
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.
format	article
author	Elizabeth A. White Karl Münger Peter M. Howley
author_facet	Elizabeth A. White Karl Münger Peter M. Howley
author_sort	Elizabeth A. White
title	High-Risk Human Papillomavirus E7 Proteins Target PTPN14 for Degradation
title_short	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_sort	high-risk human papillomavirus e7 proteins target ptpn14 for degradation
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/48b42be47f234822b503ae440d22e202
work_keys_str_mv	AT elizabethawhite highriskhumanpapillomaviruse7proteinstargetptpn14fordegradation AT karlmunger highriskhumanpapillomaviruse7proteinstargetptpn14fordegradation AT petermhowley highriskhumanpapillomaviruse7proteinstargetptpn14fordegradation
_version_	1718427454986518528

High-Risk Human Papillomavirus E7 Proteins Target PTPN14 for Degradation

Ejemplares similares