Engagement of protein kinase C-θ in interferon signaling in T-cells

Kishore K. Srivastava, Sandeep Batra, Antonella Sassano, Yongzhong Li, Beata Majchrzak, Hiroaki Kiyokawa, Amnon Altman, Eleanor N. Fish, Leonidas C. Platanias*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Protein kinase C-theta (PKC-θ) 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-θ is engaged in interferon (INF) signaling in T-cells. Both Type I (α, β) and Type II (γ) IFNs induced phosphorylation of PKC-θ in human T-cell lines and primary human T-lymphocytes. Such phosphorylation of PKC-θ resulted in activation of its kinase domain, suggesting that this kinase plays a functional role in interferon signaling. Consistent with this, inhibition of PKC-θ protein expression using small interfering RNAs (siRNA) abrogated IFN-α- and IFN-γ-dependent gene transcription via GAS elements. Similarly, blocking of PKC-θ kinase activity by overexpression of a dominant-negative PKC-θ mutant also blocked GAS-driven transcription, further demonstrating a requirement for PKC-θ in IFN-dependent transcriptional activation. The effects of PKC-θ on IFN-dependent gene transcription were not mediated by regulation of the IFN-activated STAT pathway, as siRNA-mediated PKC-θ knockdown had no effects on STAT1 phosphorylation and binding of STAT1-containing complexes to SIE/GAS elements. On the other hand, siRNA-mediated PKC-θ inhibition blocked phosphorylation/activation of MKK4, suggesting that interferon-dependent PKC-θ activation regulates downstream engagement of MAP kinase pathways. Altogether, these findings demonstrate that PKC-θ is an interferon-inducible kinase and strongly suggest that it plays an important role in the generation of interferon-responses in T-cells.

Original languageEnglish (US)
Pages (from-to)29911-29920
Number of pages10
JournalJournal of Biological Chemistry
Volume279
Issue number29
DOIs
StatePublished - Jul 16 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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