Originally published In Press as doi:10.1074/jbc.M401997200 on May 18, 2004
J. Biol. Chem., Vol. 279, Issue 29, 29911-29920, July 16, 2004
Engagement of Protein Kinase C-
in Interferon Signaling in T-cells*
Kishore K. Srivastava
,
Sandeep Batra,
Antonella Sassano,
Yongzhong Li,
Beata Majchrzak
,
Hiroaki Kiyokawa¶,
Amnon Altman||,
Eleanor N. Fish, and
Leonidas C. Platanias**
From the
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School and Lakeside Veterans Administration Medical Center, Chicago, Illinois 60611, the ¶Department of Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607, the ||Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, and the Division of Cell & Molecular Biology, Toronto Research Institute, University Network and Department of Immunology, University of Toronto, Toronto, Ontario M5G 2M1, Canada
Protein kinase C-theta (PKC-
) plays important roles in the activation and survival of lymphocytes and is the predominant PKC isoform expressed in T-cells. Interferons regulate T-cell function and activation, but the precise signaling mechanisms by which they mediate such effects have not been elucidated. We determined whether PKC- is engaged in interferon (INF) signaling in T-cells. Both Type I (
, 
) and Type II (
) IFNs induced phosphorylation of PKC- in human T-cell lines and primary human T-lymphocytes. Such phosphorylation of PKC- resulted in activation of its kinase domain, suggesting that this kinase plays a functional role in interferon signaling. Consistent with this, inhibition of PKC- protein expression using small interfering RNAs (siRNA) abrogated IFN-- and IFN--dependent gene transcription via GAS elements. Similarly, blocking of PKC- kinase activity by overexpression of a dominant-negative PKC- mutant also blocked GAS-driven transcription, further demonstrating a requirement for PKC- in IFN-dependent transcriptional activation. The effects of PKC- on IFN-dependent gene transcription were not mediated by regulation of the IFN-activated STAT pathway, as siRNA-mediated PKC- knockdown had no effects on STAT1 phosphorylation and binding of STAT1-containing complexes to SIE/GAS elements. On the other hand, siRNA-mediated PKC- inhibition blocked phosphorylation/activation of MKK4, suggesting that interferon-dependent PKC- activation regulates downstream engagement of MAP kinase pathways. Altogether, these findings demonstrate that PKC- is an interferon-inducible kinase and strongly suggest that it plays an important role in the generation of interferon-responses in T-cells.
Received for publication, February 24, 2004
, and in revised form, May 6, 2004.
* This work was supported by National Institutes of Health Grants CA77816 and CA94079 (to L. C. P.), a Merit Review Grant from the Department of Veterans Affairs (to L. C. P.), and Canadian Institutes of Health Research Grant MOP15094(to E. N. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
** To whom correspondence should be addressed: Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, 710 North Fairbanks Ave., Olson Pavilion 8250, Chicago, IL 60611. Tel.: 312-503-4267; Fax: 312-908-1372; E-mail: l-platanias{at}northwestern.edu.
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Copyright © 2004 by the American Society for Biochemistry and Molecular Biology.
