Defining the distinct, intrinsic properties of the novel type i interferon, IFNϵ

Stifter, SA; Matthews, AY; Mangan, NE; Fung, KY; Drew, A; Tate, MD; Soares Da Costa, TP; Hampsey, D; Mayall, J; Hansbro, PM; Minambres, AG; Eid, SG; Mak, J; Scoble, J; Lovrecz, G; DeWeerd, NA; Hertzog, PJ

Defining the distinct, intrinsic properties of the novel type i interferon, IFNϵ

Stifter, SA Matthews, AY Mangan, NE Fung, KY Drew, A Tate, MD Soares Da Costa, TP Hampsey, D Mayall, J Hansbro, PM

Minambres, AG Eid, SG Mak, J Scoble, J Lovrecz, G DeWeerd, NA Hertzog, PJ

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Publication Type:: Journal Article
Citation:: Journal of Biological Chemistry, 2018, 293 (9), pp. 3168 - 3179
Issue Date:: 2018-03-02

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Field	Value	Language
dc.contributor.author	Stifter, SA	en_US
dc.contributor.author	Matthews, AY	en_US
dc.contributor.author	Mangan, NE	en_US
dc.contributor.author	Fung, KY	en_US
dc.contributor.author	Drew, A	en_US
dc.contributor.author	Tate, MD	en_US
dc.contributor.author	Soares Da Costa, TP	en_US
dc.contributor.author	Hampsey, D	en_US
dc.contributor.author	Mayall, J	en_US
dc.contributor.author	Hansbro, PM https://orcid.org/0000-0002-4741-3035	en_US
dc.contributor.author	Minambres, AG	en_US
dc.contributor.author	Eid, SG	en_US
dc.contributor.author	Mak, J	en_US
dc.contributor.author	Scoble, J	en_US
dc.contributor.author	Lovrecz, G	en_US
dc.contributor.author	DeWeerd, NA	en_US
dc.contributor.author	Hertzog, PJ	en_US
dc.date.issued	2018-03-02	en_US
dc.identifier.citation	Journal of Biological Chemistry, 2018, 293 (9), pp. 3168 - 3179	en_US
dc.identifier.issn	0021-9258	en_US
dc.identifier.uri	http://hdl.handle.net/10453/128293
dc.description.abstract	© 2018 by The American Society for Biochemistry and Molecular Biology, Inc. The type I interferons (IFNs) are a family of cytokines with diverse biological activities, including antiviral, antiproliferative, and immunoregulatory functions. The discovery of the hormonally regulated, constitutively expressed IFNϵ has suggested a function for IFNs in reproductive tract homeostasis and protection from infections, but its intrinsic activities are untested. We report here the expression, purification, and functional characterization of murine IFNϵ (mIFNϵ). Recombinant mIFNϵ (rmIFNϵ) exhibited an α-helical fold characteristic of type I IFNs and bound to IFNα/β receptor 1 (IFNAR1) and IFNAR2, but, unusually, it had a preference for IFNAR1. Nevertheless, rmIFNϵ induced typical type I IFN signaling activity, including STAT1 phosphorylation and activation of canonical type I IFN signaling reporters, demonstrating that it uses the JAK-STAT signaling pathway. We also found that rmIFNϵ induces the activation of T, B, and NK cells and exhibits antiviral, antiproliferative, and antibacterial activities typical of type I IFNs, albeit with 100-1000-fold reduced potency compared with rmIFNα1 and rmIFNβ. Surprisingly, although the type I IFNs generally do not display cross-species activities, rmIFNϵ exhibited high antiviral activity on human cells, suppressing HIV replication and inducing the expression of known HIV restriction factors in human lymphocytes. Our findings define the intrinsic properties of murine IFNϵ, indicating that it distinctly interacts with IFNAR and elicits pathogen-suppressing activity with a potency enabling host defense but with limited toxicity, appropriate for a protein expressed constitutively in a sensitive mucosal site, such as the reproductive tract.	en_US
dc.relation.ispartof	Journal of Biological Chemistry	en_US
dc.relation.isbasedon	10.1074/jbc.M117.800755	en_US
dc.subject.classification	Biochemistry & Molecular Biology	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Chlamydia	en_US
dc.subject.mesh	Interferon Type I	en_US
dc.subject.mesh	Receptors, Interferon	en_US
dc.subject.mesh	Anti-Bacterial Agents	en_US
dc.subject.mesh	Antiviral Agents	en_US
dc.subject.mesh	Signal Transduction	en_US
dc.subject.mesh	Cell Proliferation	en_US
dc.subject.mesh	Immunity, Mucosal	en_US
dc.subject.mesh	Phosphorylation	en_US
dc.subject.mesh	Reproduction	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	STAT1 Transcription Factor	en_US
dc.subject.mesh	RAW 264.7 Cells	en_US
dc.subject.mesh	Protein Conformation, alpha-Helical	en_US
dc.title	Defining the distinct, intrinsic properties of the novel type i interferon, IFNϵ	en_US
dc.type	Journal Article
utslib.citation.volume	9	en_US
utslib.citation.volume	293	en_US
utslib.for	1115 Pharmacology and Pharmaceutical Sciences	en_US
utslib.for	03 Chemical Sciences	en_US
utslib.for	06 Biological Sciences	en_US
utslib.for	11 Medical and Health Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	closed_access
pubs.issue	9	en_US
pubs.publication-status	Published	en_US
pubs.volume	293	en_US

Abstract:

© 2018 by The American Society for Biochemistry and Molecular Biology, Inc. The type I interferons (IFNs) are a family of cytokines with diverse biological activities, including antiviral, antiproliferative, and immunoregulatory functions. The discovery of the hormonally regulated, constitutively expressed IFNϵ has suggested a function for IFNs in reproductive tract homeostasis and protection from infections, but its intrinsic activities are untested. We report here the expression, purification, and functional characterization of murine IFNϵ (mIFNϵ). Recombinant mIFNϵ (rmIFNϵ) exhibited an α-helical fold characteristic of type I IFNs and bound to IFNα/β receptor 1 (IFNAR1) and IFNAR2, but, unusually, it had a preference for IFNAR1. Nevertheless, rmIFNϵ induced typical type I IFN signaling activity, including STAT1 phosphorylation and activation of canonical type I IFN signaling reporters, demonstrating that it uses the JAK-STAT signaling pathway. We also found that rmIFNϵ induces the activation of T, B, and NK cells and exhibits antiviral, antiproliferative, and antibacterial activities typical of type I IFNs, albeit with 100-1000-fold reduced potency compared with rmIFNα1 and rmIFNβ. Surprisingly, although the type I IFNs generally do not display cross-species activities, rmIFNϵ exhibited high antiviral activity on human cells, suppressing HIV replication and inducing the expression of known HIV restriction factors in human lymphocytes. Our findings define the intrinsic properties of murine IFNϵ, indicating that it distinctly interacts with IFNAR and elicits pathogen-suppressing activity with a potency enabling host defense but with limited toxicity, appropriate for a protein expressed constitutively in a sensitive mucosal site, such as the reproductive tract.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/128293