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| The EMBO Journal
(2001) 20, 1310–1319, doi:10.1093/emboj/20.6.1310 |
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| Adenovirus-activated PKA and p38/MAPK pathways boost microtubule-mediated nuclear targeting of virus |
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| M. Suomalainen2, 3, M.Y. Nakano1, 3, K. Boucke1, S. Keller1 and U.F. Greber1 |
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1 University of Zürich, Institute of Zoology, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland 2 Present address: Karolinska Institute, Department of Biosciences at Novum, S-141 57 Huddinge, Sweden 3 M.Suomalainen and M.Y.Nakano contributed equally to this work To whom correspondence should be addressed U.F. Greber, ufgreber@zool.unizh.ch Received 2 November 2000; Revised 11 January 2001; Accepted 23 January 2001. |
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| Abstract |
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| 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. |
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| Keywords: adenovirus, MAPK, microtubules, PKA, regulated nuclear targeting |
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