Protein tyrosine phosphatase 1B is a key regulator of IFNAR1 endocytosis and a target for antiviral therapies

Christopher J. Carbone, Hui Zheng, Sabyasachi Bhattacharya, John R. Lewis, Alexander M. Reiter, Paula Henthorn, Zhong Yin Zhang, Darren P. Baker, Radha Ukkiramapandian, Kendra K. Bence, Serge Y. Fuchs

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Abstract

Type 1 interferons (IFN1) elicit antiviral defenses by activating the cognate receptor composed of IFN-α/β receptor chain 1 (IFNAR1) and IFNAR2. Down-regulation of this receptor occurs through IFN1-stimulated IFNAR1 ubiquitination, which exposes a Y466-based linear endocytic motif within IFNAR1 to recruitment of the adaptin protein-2 complex (AP2) and ensuing receptor endocytosis. Paradoxically, IFN1-induced Janus kinase-mediated phosphorylation of Y466 is expected to decrease its affinity for AP2 and to inhibit the endocytic rate. To explain how IFN1 promotes Y466 phosphorylation yet stimulates IFNAR1 internalization, we proposed that the activity of a protein tyrosine phosphatase (PTP) is required to enable both events by dephosphorylating Y466. An RNAi-based screen identified PTP1B as a specific regulator of IFNAR1 endocytosis stimulated by IFN1, but not by ligand-independent inducers of IFNAR1 ubiquitination. PTP1B is a promising target for treatment of obesity and diabetes; numerous research programs are aimed at identification and characterization of clinically relevant inhibitors of PTP1B. PTP1B is capable of binding and dephosphorylating IFNAR1. Genetic or pharmacologic modulation of PTP1B activity regulated IFN1 signaling in a manner dependent on the integrity of Y466 within IFNAR1 in human cells. These effectswere less evident inmouse cellswhose IFNAR1 lacks an analogous motif. PTP1B inhibitors robustly augmented the antiviral effects of IFN1 against vesicular stomatitis and hepatitis C viruses in human cells and proved beneficial in feline stomatitis patients. The clinical significance of these findings in the context of using PTP1B inhibitors to increase the therapeutic efficacy of IFN against viral infections is discussed.

Original languageEnglish (US)
Pages (from-to)19226-19231
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number47
DOIs
StatePublished - Nov 20 2012

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Carbone, C. J., Zheng, H., Bhattacharya, S., Lewis, J. R., Reiter, A. M., Henthorn, P., Zhang, Z. Y., Baker, D. P., Ukkiramapandian, R., Bence, K. K., & Fuchs, S. Y. (2012). Protein tyrosine phosphatase 1B is a key regulator of IFNAR1 endocytosis and a target for antiviral therapies. Proceedings of the National Academy of Sciences of the United States of America, 109(47), 19226-19231. https://doi.org/10.1073/pnas.1211491109