title: Protein tyrosine phosphatase 1B is a key regulator of IFNAR1 endocytosis and a target for antiviral therapies.
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 effects were less evident in mouse cells whose 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.
authors.affiliation: Mari Lowe Comparative Oncology Center and Department of Animal Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Carbone
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: John R
authors.initials: JR
authors.lastname: Lewis
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Reiter
authors.forename: Paula
authors.initials: P
authors.lastname: Henthorn
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.forename: Darren P
authors.initials: DP
authors.lastname: Baker
authors.forename: Radha
authors.initials: R
authors.lastname: Ukkiramapandian
authors.forename: Kendra K
authors.initials: KK
authors.lastname: Bence
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D053633:Receptor, Interferon alpha-beta / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; C507964:IFNAR1 protein, human; C508032:Ifnar1 protein, mouse; D008024:Ligands; D053633:Receptor, Interferon alpha-beta; D019000:Phosphotyrosine; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1