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

Abstract

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.

• Authors: Mehran Haidari, Wei Zhang, Leila Ganjehei, Muzammil Ali, Zhenping Chen
• Journal: PloS one (PLoS One) Vol. 6 Issue 6 Pg. e21444 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21731751 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Actins
• Antiviral Agents
• Myosin Light Chains
• RNA, Small Interfering
• Ribonucleoproteins
• Protein Kinase C
• Extracellular Signal-Regulated MAP Kinases
• GTP-Binding Proteins
• rhoA GTP-Binding Protein
• N-Acetylneuraminic Acid

Topics

• Actins (metabolism)
• Active Transport, Cell Nucleus (drug effects)
• Adenoviridae (drug effects, genetics)
• Animals
• Antiviral Agents (pharmacology)
• Cytoskeleton (drug effects, metabolism)
• Dogs
• Endothelial Cells (drug effects, enzymology, virology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• GTP-Binding Proteins (metabolism)
• Humans
• Influenza, Human (virology)
• Models, Biological
• Myosin Light Chains (metabolism)
• N-Acetylneuraminic Acid (metabolism)
• Orthomyxoviridae (drug effects, physiology)
• Phosphorylation (drug effects)
• Plasmids (metabolism)
• Protein Kinase C (metabolism)
• RNA, Small Interfering (metabolism)
• Ribonucleoproteins (metabolism)
• Signal Transduction (drug effects)
• Transduction, Genetic
• Umbilical Veins (cytology)
• Virus Replication (drug effects)
• rhoA GTP-Binding Protein (metabolism)