title: Viral activation of stress-regulated Rho-GTPase signaling pathway disrupts sites of mRNA degradation to influence cellular gene expression.
abstract: Viruses are useful tools that often reveal previously unrecognized levels of control within a cell. By studying the oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV), we discovered a new signaling axis in endothelial cells (ECs) that links actin cytoskeleton dynamics to post-transcriptional control of gene expression. Translational repression and rapid decay of mRNAs containing AU-rich elements (AREs) occurs in cytoplasmic RNA granules known as processing bodies (PBs). Rho-GTPase activity influences PB dynamics but mechanistic details remain obscure. We have previously shown that the KSHV Kaposin B protein blocks the degradation of ARE-mRNAs that encode potent cytokines and angiogenic factors, at least in part by preventing PB formation. Moreover, Kaposin B is sufficient to cause marked alterations in endothelial cell physiology including the formation of long parallel actin stress fibers and accelerated migration and angiogenic phenotypes. All of these phenotypes depend on Kaposin B-mediated activation of a non-canonical signaling pathway comprising the stress-inducible kinase MK2, hsp27, p115RhoGEF and RhoA. Accelerated endothelial cell migration and angiogenesis depends on the subsequent activation of the RhoA-dependent kinase ROCK, but PB disruption is ROCK-independent. In this Commentary, we discuss implications of the activation of this signaling axis, and propose mechanistic links between RhoA activation and PB dynamics.
authors.affiliation: a Department of Microbiology and Immunology ; Dalhousie University ; Halifax NS , Canada.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Corcoran
authors.affiliation: a Department of Microbiology and Immunology ; Dalhousie University ; Halifax NS , Canada.
authors.forename: Craig
authors.initials: C
authors.lastname: McCormick
mesh_terms: D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014775:Virus Activation / Q000502:physiology*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D017346:Protein Serine-Threonine Kinases; D064067:Rho Guanine Nucleotide Exchange Factors; D014764:Viral Proteins; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D000099190:MAP-Kinase-Activated Kinase 2; C057725:HSPB1 protein, human; C120136:kaposin B protein, Human herpesvirus 8; C066737:RHOA protein, human
keywords: Kaposi's sarcoma-associated herpesvirus; MK2; Rho-GTPase; cytoskeleton; p-body