Interactions of the Nipah Virus P, V, and W Proteins across the STAT Family of Transcription Factors

ABSTRACT The Nipah virus (NiV) phosphoprotein (P) gene encodes four proteins. Three of these—P, V, and W—possess a common N-terminal domain but distinct C termini. These proteins interact with immune modulators. Previous studies demonstrated that P, V, and W bind STAT1 and STAT4 and that V also inte...

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Autores principales:	Timothy R. Keiffer, Michael J. Ciancanelli, Megan R. Edwards, Christopher F. Basler
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Nipah virus STAT transcription factors interferon Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3ec80e3a593242a58ec882a593caba86
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spelling	oai:doaj.org-article:3ec80e3a593242a58ec882a593caba862021-11-15T15:31:12ZInteractions of the Nipah Virus P, V, and W Proteins across the STAT Family of Transcription Factors10.1128/mSphere.00449-202379-5042https://doaj.org/article/3ec80e3a593242a58ec882a593caba862020-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00449-20https://doaj.org/toc/2379-5042ABSTRACT The Nipah virus (NiV) phosphoprotein (P) gene encodes four proteins. Three of these—P, V, and W—possess a common N-terminal domain but distinct C termini. These proteins interact with immune modulators. Previous studies demonstrated that P, V, and W bind STAT1 and STAT4 and that V also interacts with STAT2 but not with STAT3. The STAT1 and STAT2 interactions block interferon (IFN)-induced STAT tyrosine phosphorylation. To more fully characterize the interactions of P, V, and W with the STATs, we screened for interaction of each viral protein with STATs 1 to 6 by coimmunoprecipitation. We demonstrate that NiV P, V, and W interact with STAT4 through their common N-terminal domain and block STAT4 activity, based on a STAT4 response element reporter assay. Although none of the NiV proteins interact with STAT3 or STAT6, NiV V, but not P or W, interacts with STAT5 through its unique C terminus. Furthermore, the interaction of NiV V with STAT5 was not disrupted by overexpression of the N-terminal binding STAT1 or the C-terminal binding MDA5. NiV V also inhibits a STAT5 response element reporter assay. Residues 114 to 140 of the common N-terminal domain of the NiV P gene products were found to be sufficient to bind STAT1 and STAT4. Analysis of STAT1-STAT3 chimeras suggests that the P gene products target the STAT1 SH2 domain. When fused to GST, the 114-140 peptide is sufficient to decrease STAT1 phosphorylation in IFN-β-stimulated cells, suggesting that this peptide could potentially be fused to heterologous proteins to confer inhibition of STAT1- and STAT4-dependent responses. IMPORTANCE How Nipah virus (NiV) antagonizes innate immune responses is incompletely understood. The P gene of NiV encodes the P, V, and W proteins. These proteins have a common N-terminal sequence that is sufficient to bind to STAT1 and STAT2 and block IFN-induced signal transduction. This study sought to more fully understand how P, V, and W engage with the STAT family of transcription factors to influence their functions. The results identify a novel interaction of V with STAT5 and demonstrate V inhibition of STAT5 function. We also demonstrate that the common N-terminal residues 114 to 140 of P, V, and W are critical for inhibition of STAT1 and STAT4 function, map the interaction to the SH2 region of STAT1, and show that a fusion construct with this peptide significantly inhibits cytokine-induced STAT1 phosphorylation. These data clarify how these important virulence factors modulate innate antiviral defenses.Timothy R. KeifferMichael J. CiancanelliMegan R. EdwardsChristopher F. BaslerAmerican Society for MicrobiologyarticleNipah virusSTAT transcription factorsinterferonMicrobiologyQR1-502ENmSphere, Vol 5, Iss 6 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Nipah virus STAT transcription factors interferon Microbiology QR1-502
spellingShingle	Nipah virus STAT transcription factors interferon Microbiology QR1-502 Timothy R. Keiffer Michael J. Ciancanelli Megan R. Edwards Christopher F. Basler Interactions of the Nipah Virus P, V, and W Proteins across the STAT Family of Transcription Factors
description	ABSTRACT The Nipah virus (NiV) phosphoprotein (P) gene encodes four proteins. Three of these—P, V, and W—possess a common N-terminal domain but distinct C termini. These proteins interact with immune modulators. Previous studies demonstrated that P, V, and W bind STAT1 and STAT4 and that V also interacts with STAT2 but not with STAT3. The STAT1 and STAT2 interactions block interferon (IFN)-induced STAT tyrosine phosphorylation. To more fully characterize the interactions of P, V, and W with the STATs, we screened for interaction of each viral protein with STATs 1 to 6 by coimmunoprecipitation. We demonstrate that NiV P, V, and W interact with STAT4 through their common N-terminal domain and block STAT4 activity, based on a STAT4 response element reporter assay. Although none of the NiV proteins interact with STAT3 or STAT6, NiV V, but not P or W, interacts with STAT5 through its unique C terminus. Furthermore, the interaction of NiV V with STAT5 was not disrupted by overexpression of the N-terminal binding STAT1 or the C-terminal binding MDA5. NiV V also inhibits a STAT5 response element reporter assay. Residues 114 to 140 of the common N-terminal domain of the NiV P gene products were found to be sufficient to bind STAT1 and STAT4. Analysis of STAT1-STAT3 chimeras suggests that the P gene products target the STAT1 SH2 domain. When fused to GST, the 114-140 peptide is sufficient to decrease STAT1 phosphorylation in IFN-β-stimulated cells, suggesting that this peptide could potentially be fused to heterologous proteins to confer inhibition of STAT1- and STAT4-dependent responses. IMPORTANCE How Nipah virus (NiV) antagonizes innate immune responses is incompletely understood. The P gene of NiV encodes the P, V, and W proteins. These proteins have a common N-terminal sequence that is sufficient to bind to STAT1 and STAT2 and block IFN-induced signal transduction. This study sought to more fully understand how P, V, and W engage with the STAT family of transcription factors to influence their functions. The results identify a novel interaction of V with STAT5 and demonstrate V inhibition of STAT5 function. We also demonstrate that the common N-terminal residues 114 to 140 of P, V, and W are critical for inhibition of STAT1 and STAT4 function, map the interaction to the SH2 region of STAT1, and show that a fusion construct with this peptide significantly inhibits cytokine-induced STAT1 phosphorylation. These data clarify how these important virulence factors modulate innate antiviral defenses.
format	article
author	Timothy R. Keiffer Michael J. Ciancanelli Megan R. Edwards Christopher F. Basler
author_facet	Timothy R. Keiffer Michael J. Ciancanelli Megan R. Edwards Christopher F. Basler
author_sort	Timothy R. Keiffer
title	Interactions of the Nipah Virus P, V, and W Proteins across the STAT Family of Transcription Factors
title_short	Interactions of the Nipah Virus P, V, and W Proteins across the STAT Family of Transcription Factors
title_full	Interactions of the Nipah Virus P, V, and W Proteins across the STAT Family of Transcription Factors
title_fullStr	Interactions of the Nipah Virus P, V, and W Proteins across the STAT Family of Transcription Factors
title_full_unstemmed	Interactions of the Nipah Virus P, V, and W Proteins across the STAT Family of Transcription Factors
title_sort	interactions of the nipah virus p, v, and w proteins across the stat family of transcription factors
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/3ec80e3a593242a58ec882a593caba86
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Interactions of the Nipah Virus P, V, and W Proteins across the STAT Family of Transcription Factors

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