Inhibition of MLC phosphorylation restricts replication of influenza virus--a mechanism of action for anti-influenza agents.

Influenza A viruses are a severe threat worldwide, causing large epidemics that kill thousands every year. Prevention of influenza infection is complicated by continuous viral antigenic changes. Newer anti-influenza agents include MEK/ERK and protein kinase C inhibitors; however, the downstream effe...

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Main Authors: Mehran Haidari, Wei Zhang, Leila Ganjehei, Muzammil Ali, Zhenping Chen
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2011-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC3121769?pdf=render
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author Mehran Haidari
Wei Zhang
Leila Ganjehei
Muzammil Ali
Zhenping Chen
author_facet Mehran Haidari
Wei Zhang
Leila Ganjehei
Muzammil Ali
Zhenping Chen
author_sort Mehran Haidari
collection DOAJ
description Influenza A viruses are a severe threat worldwide, causing large epidemics that kill thousands every year. Prevention of influenza infection is complicated by continuous viral antigenic changes. Newer anti-influenza agents include MEK/ERK and protein kinase C inhibitors; however, the downstream effectors of these pathways have not been determined. In this study, we identified a common mechanism for the inhibitory effects of a significant group of anti-influenza agents. Our studies showed that influenza infection activates a series of signaling pathways that converge to induce myosin light chain (MLC) phosphorylation and remodeling of the actin cytoskeleton. Inhibiting MLC phosphorylation by blocking RhoA/Rho kinase, phospholipase C/protein kinase C, and HRas/Raf/MEK/ERK pathways with the use of genetic or chemical manipulation leads to the inhibition of influenza proliferation. In contrast, the induction of MLC phosphorylation enhances influenza proliferation, as does activation of the HRas/Raf/MEK/ERK signaling pathway. This effect is attenuated by inhibiting MLC phosphorylation. Additionally, in intracellular trafficking studies, we found that the nuclear export of influenza ribonucleoprotein depends on MLC phosphorylation. Our studies provide evidence that modulation of MLC phosphorylation is an underlying mechanism for the inhibitory effects of many anti-influenza compounds.
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spelling doaj.art-1d179fe06b3c4951a6ea0606f0ca72e02022-12-21T23:54:48ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0166e2144410.1371/journal.pone.0021444Inhibition of MLC phosphorylation restricts replication of influenza virus--a mechanism of action for anti-influenza agents.Mehran HaidariWei ZhangLeila GanjeheiMuzammil AliZhenping ChenInfluenza A viruses are a severe threat worldwide, causing large epidemics that kill thousands every year. Prevention of influenza infection is complicated by continuous viral antigenic changes. Newer anti-influenza agents include MEK/ERK and protein kinase C inhibitors; however, the downstream effectors of these pathways have not been determined. In this study, we identified a common mechanism for the inhibitory effects of a significant group of anti-influenza agents. Our studies showed that influenza infection activates a series of signaling pathways that converge to induce myosin light chain (MLC) phosphorylation and remodeling of the actin cytoskeleton. Inhibiting MLC phosphorylation by blocking RhoA/Rho kinase, phospholipase C/protein kinase C, and HRas/Raf/MEK/ERK pathways with the use of genetic or chemical manipulation leads to the inhibition of influenza proliferation. In contrast, the induction of MLC phosphorylation enhances influenza proliferation, as does activation of the HRas/Raf/MEK/ERK signaling pathway. This effect is attenuated by inhibiting MLC phosphorylation. Additionally, in intracellular trafficking studies, we found that the nuclear export of influenza ribonucleoprotein depends on MLC phosphorylation. Our studies provide evidence that modulation of MLC phosphorylation is an underlying mechanism for the inhibitory effects of many anti-influenza compounds.http://europepmc.org/articles/PMC3121769?pdf=render
spellingShingle Mehran Haidari
Wei Zhang
Leila Ganjehei
Muzammil Ali
Zhenping Chen
Inhibition of MLC phosphorylation restricts replication of influenza virus--a mechanism of action for anti-influenza agents.
PLoS ONE
title Inhibition of MLC phosphorylation restricts replication of influenza virus--a mechanism of action for anti-influenza agents.
title_full Inhibition of MLC phosphorylation restricts replication of influenza virus--a mechanism of action for anti-influenza agents.
title_fullStr Inhibition of MLC phosphorylation restricts replication of influenza virus--a mechanism of action for anti-influenza agents.
title_full_unstemmed Inhibition of MLC phosphorylation restricts replication of influenza virus--a mechanism of action for anti-influenza agents.
title_short Inhibition of MLC phosphorylation restricts replication of influenza virus--a mechanism of action for anti-influenza agents.
title_sort inhibition of mlc phosphorylation restricts replication of influenza virus a mechanism of action for anti influenza agents
url http://europepmc.org/articles/PMC3121769?pdf=render
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