The Master Regulator of the Cellular Stress Response (HSF1) Is Critical for Orthopoxvirus Infection

The genus Orthopoxviridae contains a diverse group of human pathogens including monkeypox, smallpox and vaccinia. These viruses are presumed to be less dependent on host functions than other DNA viruses because they have large genomes and replicate in the cytoplasm, but a detailed understanding of t...

Full description

Bibliographic Details
Main Authors:	Filone, Claire Marie, Caballero, Ignacio S., Dower, Ken, Mendillo, Marc L., Cowley, Glenn S., Santagata, Sandro, Rozelle, Daniel K., Yen, Judy, Rubins, Kathleen H., Hacohen, Nir, Root, David E., Hensley, Lisa E., Connor, John
Format:	Online
Language:	English
Published:	Public Library of Science 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916389/

id	pubmed-3916389
recordtype	oai_dc
spelling	pubmed-39163892014-02-10 The Master Regulator of the Cellular Stress Response (HSF1) Is Critical for Orthopoxvirus Infection Filone, Claire Marie Caballero, Ignacio S. Dower, Ken Mendillo, Marc L. Cowley, Glenn S. Santagata, Sandro Rozelle, Daniel K. Yen, Judy Rubins, Kathleen H. Hacohen, Nir Root, David E. Hensley, Lisa E. Connor, John Research Article The genus Orthopoxviridae contains a diverse group of human pathogens including monkeypox, smallpox and vaccinia. These viruses are presumed to be less dependent on host functions than other DNA viruses because they have large genomes and replicate in the cytoplasm, but a detailed understanding of the host factors required by orthopoxviruses is lacking. To address this topic, we performed an unbiased, genome-wide pooled RNAi screen targeting over 17,000 human genes to identify the host factors that support orthopoxvirus infection. We used secondary and tertiary assays to validate our screen results. One of the strongest hits was heat shock factor 1 (HSF1), the ancient master regulator of the cytoprotective heat-shock response. In investigating the behavior of HSF1 during vaccinia infection, we found that HSF1 was phosphorylated, translocated to the nucleus, and increased transcription of HSF1 target genes. Activation of HSF1 was supportive for virus replication, as RNAi knockdown and HSF1 small molecule inhibition prevented orthopoxvirus infection. Consistent with its role as a transcriptional activator, inhibition of several HSF1 targets also blocked vaccinia virus replication. These data show that orthopoxviruses co-opt host transcriptional responses for their own benefit, thereby effectively extending their functional genome to include genes residing within the host DNA. The dependence on HSF1 and its chaperone network offers multiple opportunities for antiviral drug development. Public Library of Science 2014-02-06 /pmc/articles/PMC3916389/ /pubmed/24516381 http://dx.doi.org/10.1371/journal.ppat.1003904 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Filone, Claire Marie Caballero, Ignacio S. Dower, Ken Mendillo, Marc L. Cowley, Glenn S. Santagata, Sandro Rozelle, Daniel K. Yen, Judy Rubins, Kathleen H. Hacohen, Nir Root, David E. Hensley, Lisa E. Connor, John
spellingShingle	Filone, Claire Marie Caballero, Ignacio S. Dower, Ken Mendillo, Marc L. Cowley, Glenn S. Santagata, Sandro Rozelle, Daniel K. Yen, Judy Rubins, Kathleen H. Hacohen, Nir Root, David E. Hensley, Lisa E. Connor, John The Master Regulator of the Cellular Stress Response (HSF1) Is Critical for Orthopoxvirus Infection
author_facet	Filone, Claire Marie Caballero, Ignacio S. Dower, Ken Mendillo, Marc L. Cowley, Glenn S. Santagata, Sandro Rozelle, Daniel K. Yen, Judy Rubins, Kathleen H. Hacohen, Nir Root, David E. Hensley, Lisa E. Connor, John
author_sort	Filone, Claire Marie
title	The Master Regulator of the Cellular Stress Response (HSF1) Is Critical for Orthopoxvirus Infection
title_short	The Master Regulator of the Cellular Stress Response (HSF1) Is Critical for Orthopoxvirus Infection
title_full	The Master Regulator of the Cellular Stress Response (HSF1) Is Critical for Orthopoxvirus Infection
title_fullStr	The Master Regulator of the Cellular Stress Response (HSF1) Is Critical for Orthopoxvirus Infection
title_full_unstemmed	The Master Regulator of the Cellular Stress Response (HSF1) Is Critical for Orthopoxvirus Infection
title_sort	master regulator of the cellular stress response (hsf1) is critical for orthopoxvirus infection
description	The genus Orthopoxviridae contains a diverse group of human pathogens including monkeypox, smallpox and vaccinia. These viruses are presumed to be less dependent on host functions than other DNA viruses because they have large genomes and replicate in the cytoplasm, but a detailed understanding of the host factors required by orthopoxviruses is lacking. To address this topic, we performed an unbiased, genome-wide pooled RNAi screen targeting over 17,000 human genes to identify the host factors that support orthopoxvirus infection. We used secondary and tertiary assays to validate our screen results. One of the strongest hits was heat shock factor 1 (HSF1), the ancient master regulator of the cytoprotective heat-shock response. In investigating the behavior of HSF1 during vaccinia infection, we found that HSF1 was phosphorylated, translocated to the nucleus, and increased transcription of HSF1 target genes. Activation of HSF1 was supportive for virus replication, as RNAi knockdown and HSF1 small molecule inhibition prevented orthopoxvirus infection. Consistent with its role as a transcriptional activator, inhibition of several HSF1 targets also blocked vaccinia virus replication. These data show that orthopoxviruses co-opt host transcriptional responses for their own benefit, thereby effectively extending their functional genome to include genes residing within the host DNA. The dependence on HSF1 and its chaperone network offers multiple opportunities for antiviral drug development.
publisher	Public Library of Science
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916389/
_version_	1612055869975953408

The Master Regulator of the Cellular Stress Response (HSF1) Is Critical for Orthopoxvirus Infection

Similar Items