The <named-content content-type="genus-species">Mus musculus</named-content> Papillomavirus Type 1 E7 Protein Binds to the Retinoblastoma Tumor Suppressor: Implications for Viral Pathogenesis

ABSTRACT The species specificity of papillomaviruses has been a significant roadblock for performing in vivo pathogenesis studies in common model organisms. The Mus musculus papillomavirus type 1 (MmuPV1) causes cutaneous papillomas that can progress to squamous cell carcinomas in laboratory mice. T...

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Autores principales:	Tao Wei, Miranda Grace, Aayushi Uberoi, James C. Romero-Masters, Denis Lee, Paul F. Lambert, Karl Munger
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	papillomavirus viral pathogenesis retinoblastoma tumor suppressor E7 MmuPV1 host-pathogen interactions Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ef1292efa7fb4e6381ea52dd70d70fbe
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spelling	oai:doaj.org-article:ef1292efa7fb4e6381ea52dd70d70fbe2021-11-10T18:37:52ZThe <named-content content-type="genus-species">Mus musculus</named-content> Papillomavirus Type 1 E7 Protein Binds to the Retinoblastoma Tumor Suppressor: Implications for Viral Pathogenesis10.1128/mBio.02277-212150-7511https://doaj.org/article/ef1292efa7fb4e6381ea52dd70d70fbe2021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02277-21https://doaj.org/toc/2150-7511ABSTRACT The species specificity of papillomaviruses has been a significant roadblock for performing in vivo pathogenesis studies in common model organisms. The Mus musculus papillomavirus type 1 (MmuPV1) causes cutaneous papillomas that can progress to squamous cell carcinomas in laboratory mice. The papillomavirus E6 and E7 genes encode proteins that establish and maintain a cellular milieu that allows for viral genome synthesis and viral progeny synthesis in growth-arrested, terminally differentiated keratinocytes. The E6 and E7 proteins provide this activity by binding to and functionally reprogramming key cellular regulatory proteins. The MmuPV1 E7 protein lacks the canonical LXCXE motif that mediates the binding of multiple viral oncoproteins to the cellular retinoblastoma tumor suppressor protein, RB1. Our proteomic experiments, however, revealed that MmuPV1 E7 still interacts with RB1. We show that MmuPV1 E7 interacts through its C terminus with the C-terminal domain of RB1. Binding of MmuPV1 E7 to RB1 did not cause significant activation of E2F-regulated cellular genes. MmuPV1 E7 expression was shown to be essential for papilloma formation. Experimental infection of mice with MmuPV1 expressing an E7 mutant that is defective for binding to RB1 caused delayed onset, lower incidence, and smaller sizes of papillomas. Our results demonstrate that the MmuPV1 E7 gene is essential and that targeting noncanonical activities of RB1, which are independent of RB1’s ability to modulate the expression of E2F-regulated genes, contribute to papillomavirus-mediated pathogenesis. IMPORTANCE Papillomavirus infections cause a variety of epithelial hyperplastic lesions, or warts. While most warts are benign, some papillomaviruses cause lesions that can progress to squamous cell carcinomas, and approximately 5% of all human cancers are caused by human papillomavirus (HPV) infections. The papillomavirus E6 and E7 proteins are thought to function to reprogram host epithelial cells to enable viral genome replication in terminally differentiated, normally growth-arrested cells. E6 and E7 lack enzymatic activities and function by interacting and functionally altering host cell regulatory proteins. Many cellular proteins that can interact with E6 and E7 have been identified, but the biological relevance of these interactions for viral pathogenesis has not been determined. This is because papillomaviruses are species specific and do not infect heterologous hosts. Here, we use a recently established mouse papillomavirus (MmuPV1) model to investigate the role of the E7 protein in viral pathogenesis. We show that MmuPV1 E7 is necessary for papilloma formation. The retinoblastoma tumor suppressor protein (RB1) is targeted by many papillomaviral E7 proteins, including cancer-associated HPVs. We show that MmuPV1 E7 can bind RB1 and that infection with a mutant MmuPV1 virus that expresses an RB1 binding-defective E7 mutant caused smaller and fewer papillomas that arise with delayed kinetics.Tao WeiMiranda GraceAayushi UberoiJames C. Romero-MastersDenis LeePaul F. LambertKarl MungerAmerican Society for Microbiologyarticlepapillomavirusviral pathogenesisretinoblastoma tumor suppressorE7MmuPV1host-pathogen interactionsMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	papillomavirus viral pathogenesis retinoblastoma tumor suppressor E7 MmuPV1 host-pathogen interactions Microbiology QR1-502
spellingShingle	papillomavirus viral pathogenesis retinoblastoma tumor suppressor E7 MmuPV1 host-pathogen interactions Microbiology QR1-502 Tao Wei Miranda Grace Aayushi Uberoi James C. Romero-Masters Denis Lee Paul F. Lambert Karl Munger The <named-content content-type="genus-species">Mus musculus</named-content> Papillomavirus Type 1 E7 Protein Binds to the Retinoblastoma Tumor Suppressor: Implications for Viral Pathogenesis
description	ABSTRACT The species specificity of papillomaviruses has been a significant roadblock for performing in vivo pathogenesis studies in common model organisms. The Mus musculus papillomavirus type 1 (MmuPV1) causes cutaneous papillomas that can progress to squamous cell carcinomas in laboratory mice. The papillomavirus E6 and E7 genes encode proteins that establish and maintain a cellular milieu that allows for viral genome synthesis and viral progeny synthesis in growth-arrested, terminally differentiated keratinocytes. The E6 and E7 proteins provide this activity by binding to and functionally reprogramming key cellular regulatory proteins. The MmuPV1 E7 protein lacks the canonical LXCXE motif that mediates the binding of multiple viral oncoproteins to the cellular retinoblastoma tumor suppressor protein, RB1. Our proteomic experiments, however, revealed that MmuPV1 E7 still interacts with RB1. We show that MmuPV1 E7 interacts through its C terminus with the C-terminal domain of RB1. Binding of MmuPV1 E7 to RB1 did not cause significant activation of E2F-regulated cellular genes. MmuPV1 E7 expression was shown to be essential for papilloma formation. Experimental infection of mice with MmuPV1 expressing an E7 mutant that is defective for binding to RB1 caused delayed onset, lower incidence, and smaller sizes of papillomas. Our results demonstrate that the MmuPV1 E7 gene is essential and that targeting noncanonical activities of RB1, which are independent of RB1’s ability to modulate the expression of E2F-regulated genes, contribute to papillomavirus-mediated pathogenesis. IMPORTANCE Papillomavirus infections cause a variety of epithelial hyperplastic lesions, or warts. While most warts are benign, some papillomaviruses cause lesions that can progress to squamous cell carcinomas, and approximately 5% of all human cancers are caused by human papillomavirus (HPV) infections. The papillomavirus E6 and E7 proteins are thought to function to reprogram host epithelial cells to enable viral genome replication in terminally differentiated, normally growth-arrested cells. E6 and E7 lack enzymatic activities and function by interacting and functionally altering host cell regulatory proteins. Many cellular proteins that can interact with E6 and E7 have been identified, but the biological relevance of these interactions for viral pathogenesis has not been determined. This is because papillomaviruses are species specific and do not infect heterologous hosts. Here, we use a recently established mouse papillomavirus (MmuPV1) model to investigate the role of the E7 protein in viral pathogenesis. We show that MmuPV1 E7 is necessary for papilloma formation. The retinoblastoma tumor suppressor protein (RB1) is targeted by many papillomaviral E7 proteins, including cancer-associated HPVs. We show that MmuPV1 E7 can bind RB1 and that infection with a mutant MmuPV1 virus that expresses an RB1 binding-defective E7 mutant caused smaller and fewer papillomas that arise with delayed kinetics.
format	article
author	Tao Wei Miranda Grace Aayushi Uberoi James C. Romero-Masters Denis Lee Paul F. Lambert Karl Munger
author_facet	Tao Wei Miranda Grace Aayushi Uberoi James C. Romero-Masters Denis Lee Paul F. Lambert Karl Munger
author_sort	Tao Wei
title	The <named-content content-type="genus-species">Mus musculus</named-content> Papillomavirus Type 1 E7 Protein Binds to the Retinoblastoma Tumor Suppressor: Implications for Viral Pathogenesis
title_short	The <named-content content-type="genus-species">Mus musculus</named-content> Papillomavirus Type 1 E7 Protein Binds to the Retinoblastoma Tumor Suppressor: Implications for Viral Pathogenesis
title_full	The <named-content content-type="genus-species">Mus musculus</named-content> Papillomavirus Type 1 E7 Protein Binds to the Retinoblastoma Tumor Suppressor: Implications for Viral Pathogenesis
title_fullStr	The <named-content content-type="genus-species">Mus musculus</named-content> Papillomavirus Type 1 E7 Protein Binds to the Retinoblastoma Tumor Suppressor: Implications for Viral Pathogenesis
title_full_unstemmed	The <named-content content-type="genus-species">Mus musculus</named-content> Papillomavirus Type 1 E7 Protein Binds to the Retinoblastoma Tumor Suppressor: Implications for Viral Pathogenesis
title_sort	<named-content content-type="genus-species">mus musculus</named-content> papillomavirus type 1 e7 protein binds to the retinoblastoma tumor suppressor: implications for viral pathogenesis
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/ef1292efa7fb4e6381ea52dd70d70fbe
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The <named-content content-type="genus-species">Mus musculus</named-content> Papillomavirus Type 1 E7 Protein Binds to the Retinoblastoma Tumor Suppressor: Implications for Viral Pathogenesis

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