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Regulated proteolysis of the IFNaR2 subunit of the interferon-alpha receptor

Oncogene volume 23, pages 7076–7086 (2004)Cite this article

Abstract

The type I interferons (IFNs) bind surface receptors, induce JAK kinases and activate STAT transcription factors to stimulate the transcription of genes downstream of IFN-stimulated response elements (ISREs). In this study, we demonstrate that IFNaR2, a subunit of the type I IFN receptor, is proteolytically cleaved in a regulated manner. Immunoblotting shows that multi-step cleavage occurs in response to phorbol ester (PMA) and IFN-α, generating both a transmembrane ‘stub’ and the intracellular domain (ICD), similar to Notch proteolysis. Isolated membrane fractions process IFNaR2 to release the ICD. A chimeric receptor construct is utilized to show that cleavage requires the presenilins and occurs in response to epidermal growth factor and protein kinase C-δ overexpression, as well as PMA and type I IFNs. Fluorescence microscopy demonstrates that a green fluorescent protein–ICD fusion localizes predominantly to the nucleus. A fusion between the ICD and the Gal4 DNA-binding domain represses transcription, in a histone deacetylase-dependent manner, of a Gal4 upstream activating sequence-regulated reporter, while overexpression of the ICD alone represses transcription of a reporter linked to an ISRE. Proteolytic cleavage events may facilitate receptor turnover or, more likely, function as a mechanism for signaling similar to that employed by Notch and the Alzheimer's precursor protein.

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Acknowledgements

We thank H Young and D Selkoe for cell lines; B Weinstein, J Chan and G Carpenter for plasmids; K Nastiuk for antibody and M Brunda and J Rosa for IFNα. This work was supported by a grant from the National Institutes of Health (CA56862) to JJK.

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Authors and Affiliations

  1. Department of Pathology, College of Medicine, University of California, Irvine, 92697, CA, USA

    Abu Z M Saleh, Aaron T Fang, Allison E Arch & John J Krolewski

  2. Department of Biological Chemistry, College of Medicine, University of California, Irvine, 92697, CA, USA

    Divas Neupane, Ashraf El Fiky & John J Krolewski

  3. Chao Family Comprehensive Cancer Center, College of Medicine, University of California, Irvine, 92697, CA, USA

    John J Krolewski

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  1. Abu Z M Saleh
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  2. Aaron T Fang
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Correspondence to John J Krolewski.

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Saleh, A., Fang, A., Arch, A. et al. Regulated proteolysis of the IFNaR2 subunit of the interferon-alpha receptor. Oncogene 23, 7076–7086 (2004). https://doi.org/10.1038/sj.onc.1207955

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