Ligand-Stimulated Downregulation of the Alpha Interferon Receptor: Role of Protein Kinase D2

Abstract

Alpha interferon (IFN-α) controls homeostasis of hematopoietic stem cells, regulates antiviral resistance, inhibits angiogenesis, and suppresses tumor growth. This cytokine is often used to treat cancers and chronic viral infections. The extent of cellular responses to IFN-α is limited by the IFN-induced ubiquitination and degradation of the IFN-α/β receptor chain 1 (IFNAR1) chain of the cognate receptor. IFNAR1 ubiquitination is facilitated by the βTrcp E3 ubiquitin ligase that is recruited to IFNAR1 upon its degron phosphorylation, which is induced by the ligand. Here we report identification of protein kinase D2 (PKD2) as a kinase that mediates the ligand-inducible phosphorylation of IFNAR1 degron and enables binding of βTrcp to the receptor. Treatment of cells with IFN-α induces catalytic activity of PKD2 and stimulates its interaction with IFNAR1. Expression and kinase activity of PKD2 are required for the ligand-inducible stimulation of IFNAR1 ubiquitination and endocytosis and for accelerated proteolytic turnover of IFNAR1. Furthermore, inhibition or knockdown of PKD2 robustly augments intracellular signaling induced by IFN-α and increases the efficacy of its antiviral effects. The mechanisms of the ligand-inducible elimination of IFNAR1 are discussed, along with the potential medical significance of this regulation.

ACKNOWLEDGMENTS

We thank J. A. Diehl, R. Harty, M. Herlyn, C. Horvath, J. Krolewski, V. Malhotra, S. Pellegrini and G. Stark for the reagents. We are also grateful to Z. Ronai, A. Weissman, J. A. Diehl, and V. S. Spiegelman for helpful comments and suggestions.

We all declare no conflict of interest, apart from D.P.B., who is an employee of Biogen Idec and owns shares of Biogen Idec stock.

This work was supported by Public Health Service grants CA092900 and CA142425 from the National Cancer Institute and funds from The Mari Lowe Center for Comparative Oncology Research (to S.F.).

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01154-10.