Role of p38alpha Map kinase in Type I interferon signaling.
Multiple signaling pathways are activated during engagement of the Type I interferon (IFN) receptor to mediate biological responses, including the Jak-Stat and Rac1/p38 Map kinase signaling cascades. In the present study we sought to determine the functional relevance of the p38alpha isoform in IFN signaling, using cells from mouse embryos with targeted disruption of the p38alpha gene. Our data demonstrate that p38alpha activation is essential for Type I IFN-dependent transcriptional regulation via ISRE or GAS elements. On the other hand, the function of p38alpha is not required for IFN-dependent Ser727 or Tyr701 phosphorylation of Stat1 and does not impact on the formation of ISGF3 or SIF nuclear binding complexes. In efforts to identify downstream effectors of p38 that may mediate IFN-dependent transcriptional responses, we found that IFNalpha activates the kinase Msk1, a known regulator of histone phosphorylation and chromatin remodeling. In other studies, we demonstrate that Type I IFN-dependent activation of the kinases MapKapK-2 and MapKapK-3 is defective in the absence of p38alpha, while Type I IFN-dependent antiviral properties are decreased in cells with targeted disruption of the MapKapK-2 gene. Altogether, our data establish that the p38alpha Map kinase pathway regulates activation of downstream effectors that participate in the induction of IFN-dependent gene transcription, to mediate IFN-responses.
Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School and Lakeside Veterans Administration Medical Center, Chicago, Illinois 60611, USA.
Yongzhong
Y
Li
Antonella
A
Sassano
Beata
B
Majchrzak
Dilip K
DK
Deb
David E
DE
Levy
Matthias
M
Gaestel
Angel R
AR
Nebreda
Eleanor N
EN
Fish
Leonidas C
LC
Platanias
D000818:Animals; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007370:Interferon Type I / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D009995:Osmosis; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013312:Stress, Physiological; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry; D000099190:MAP-Kinase-Activated Kinase 2
D002843:Chromatin; D007370:Interferon Type I; D007371:Interferon-gamma; D047908:Intracellular Signaling Peptides and Proteins; D008156:Luciferases; D048308:Mitogen-Activated Protein Kinase 14; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; D012694:Serine; D014443:Tyrosine; D000099190:MAP-Kinase-Activated Kinase 2; C098416:MAP-kinase-activated kinase 3