Protein kinase C-delta (PKC-delta ) is activated by type I interferons and mediates phosphorylation of Stat1 on serine 727.
It is well established that engagement of the Type I interferon (IFN) receptor results in activation of JAKs (Janus kinases), which in turn regulate tyrosine phosphorylation of STAT proteins. Subsequently, the IFN-dependent tyrosine-phosphorylated/activated STATs translocate to the nucleus to regulate gene transcription. In addition to tyrosine phosphorylation, phosphorylation of Stat1 on serine 727 is essential for induction of its transcriptional activity, but the IFNalpha-dependent serine kinase that regulates such phosphorylation remains unknown. In the present study we provide evidence that PKC-delta, a member of the protein kinase C family of proteins, is activated during engagement of the Type I IFN receptor and associates with Stat1. Such an activation of PKC-delta appears to be critical for phosphorylation of Stat1 on serine 727, as inhibition of PKC-delta activation diminishes the IFNalpha- or IFNbeta-dependent serine phosphorylation of Stat1. In addition, treatment of cells with the PKC-delta inhibitor rottlerin or the expression of a dominant-negative PKC-delta mutant results in inhibition of IFNalpha- and IFNbeta-dependent gene transcription via ISRE or GAS elements. Interestingly, PKC-delta inhibition also blocks activation of the p38 MAP kinase, the function of which is required for IFNalpha-dependent transcriptional regulation, suggesting a dual mechanism by which this kinase participates in the generation of IFNalpha responses. Altogether, these findings indicate that PKC-delta functions as a serine kinase for Stat1 and an upstream regulator of the p38 MAP kinase and plays an important role in the induction of Type I IFN-biological responses.
Uddin
Shahab
S
Section of Hematology-Oncology, Department of Medicine, University of Illinois at Chicago and West Side Veterans Administration Medical Center, Chicago, Illinois 60607, USA.
Sassano
Antonella
A
Deb
Dilip K
DK
Verma
Amit
A
Majchrzak
Beata
B
Rahman
Arshad
A
Malik
Asrar B
AB
Fish
Eleanor N
EN
Platanias
Leonidas C
LC
D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007370:Interferon Type I / Q000502:physiology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051745:Protein Kinase C-delta; D050794:STAT1 Transcription Factor; D012694:Serine / Q000378:metabolism*; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D017931:DNA Primers; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007370:Interferon Type I; D007527:Isoenzymes; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D012694:Serine; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases