Adenovirus-activated PKA and p38/MAPK pathways boost microtubule-mediated nuclear targeting of virus.
Nuclear targeting of adenovirus is mediated by the microtubule-dependent, minus-end-directed motor complex dynein/dynactin, in competition with plus- end-directed motility. We demonstrate that adenovirus transiently activates two distinct signaling pathways to enhance nuclear targeting. The first pathway activates integrins and cAMP-dependent protein kinase A (PKA). The second pathway activates the p38/MAP kinase and the downstream MAPKAP kinase 2 (MK2), dependent on the p38/MAPK kinase MKK6, but independent of integrins and PKA. Motility measurements in PKA-inhibited, p38-inhibited or MK2-lacking (MK2(-/-)) cells indicate that PKA and p38 stimulated both the frequency and velocity of minus-end-directed viral motility without affecting the perinuclear localization of transferrin-containing endosomal vesicles. p38 also suppressed lateral viral motilities and MK2 boosted the frequency of minus-end-directed virus transport. Nuclear targeting of adenovirus was rescued in MK2(-/-) cells by overexpression of hsp27, an MK2 target that enhances actin metabolism. Our results demonstrate that complementary activities of PKA, p38 and MK2 tip the transport balance of adenovirus towards the nucleus and thus enhance infection.
Suomalainen
M
M
University of Zürich, Institute of Zoology, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Nakano
M Y
MY
Boucke
K
K
Keller
S
S
Greber
U F
UF
D000260:Adenoviruses, Human / Q000254:growth & development*; D000818:Animals; D001692:Biological Transport; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002467:Cell Nucleus / Q000821:virology*; D002477:Cells; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D055551:HSP27 Heat-Shock Proteins; D006367:HeLa Cells; D006360:Heat-Shock Proteins; D006801:Humans; D016023:Integrins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D048669:MAP Kinase Kinase 6; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018832:Molecular Chaperones; D009068:Movement; D009363:Neoplasm Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; D048669:MAP Kinase Kinase 6; D020928:Mitogen-Activated Protein Kinases; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C057725:HSPB1 protein, human; C486113:Hsbp1 protein, mouse; C482566:MAP2K6 protein, human; C482567:Map2k6 protein, mouse