ABSTRACT
UNLABELLED: Clinical importance of myocarditis, predominantly caused by coxsackievirus B3 (CVB3), is recently rising. However, a detailed mechanism of pathogenesis of CVB3 myocarditis still needs to be clarified. Recently, it has been reported that histone modifications including acetylation are involved in coxsackievirus replication. To examine whether the CVB3 replication requires histone acetylation, histone deacetylase (HDAC) inhibitors were employed. We found that the HDAC2 activity increased in virus-infected cells at 12 hrs p.i. and that HDAC inhibitors suppressed the virus replication in vitro. This suggests that the HDAC2 activity may be required for the virus replication. Eventually, a HDAC inhibitor trichostatin A protected against CVB3-induced myocardial injury in vivo. Our results suggest that HDAC may be a novel therapeutic target for treating viral myocarditis. KEYWORDS: coxsackievirus B3; histone acetyltransferase; histone deacetylase; HDAC inhibitors, trichostatin A; apicidin; valproic acid; shRNA; myocarditis; mouse.
Subject(s)
Enterovirus B, Human/drug effects , Enterovirus B, Human/physiology , Enterovirus Infections/prevention & control , Histone Deacetylase Inhibitors/administration & dosage , Hydroxamic Acids/administration & dosage , Myocarditis/prevention & control , Virus Replication , Animals , Coxsackievirus Infections , Enterovirus B, Human/genetics , Enterovirus Infections/enzymology , Enterovirus Infections/genetics , Enterovirus Infections/virology , HeLa Cells , Histone Deacetylase 2/genetics , Histone Deacetylase 2/metabolism , Humans , Male , Mice , Mice, Inbred BALB C , Myocarditis/enzymology , Myocarditis/genetics , Myocarditis/virologySubject(s)
Anti-Allergic Agents/chemistry , Anti-Allergic Agents/pharmacology , Basidiomycota/chemistry , Intracellular Signaling Peptides and Proteins/metabolism , Mast Cells/drug effects , Protein-Tyrosine Kinases/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Antigens/immunology , Cell Degranulation/drug effects , Cell Degranulation/immunology , Cell Line, Tumor , Hypersensitivity/enzymology , Hypersensitivity/immunology , Mast Cells/enzymology , Mast Cells/immunology , Phosphorylation/drug effects , Rats , Signal Transduction/drug effects , Syk KinaseABSTRACT
P21-activated kinases (Paks), a family of serine/threonine kinases, are effectors of the Rho GTPases Cdc42 and Rac1. Mammalian Pak1 and Pak homologs in simple eukaryotes are implicated in controlling G(2)/M transition and/or mitosis. Another serine/threonine kinase, polo-like kinase 1 (Plk1), is an important regulator of mitotic events, such as centrosome maturation, mitotic entry, spindle formation, sister chromatid cohesion and cytokinesis. Plk1 phosphorylation is thought to be one of the critical regulatory events leading to these Plk1-mediated functions. We show here that Pak1 is required for cell proliferation, mitotic progression and Plk1 activity in HeLa cells. Gain or loss of Pak function directly impacted phosphorylation and activity of Plk1. Phosphorylation of Plk1 on Ser 49 is important for metaphase-associated events. Inhibition of Pak activity leads to delay in G(2)/M progression and abnormal spindle formation, mirroring some attributes of Plk1 deregulation. Our results reveal a role for Pak in regulating Plk1 activity and mitotic progression, and connect Pak to the complex protein interaction network enabling cell division.
