STAT3 Linked to Interferon-Induced Antiviral Response

A recent paper reported the discovery of a previously unknown anti-viral role for the STAT3 (signal transducer and activator of transcription 3) protein, which links it to the interferon-alpha (IFN-alpha) immune signaling pathway.

Interferon (IFN)-alpha induces a wide spectrum of anti-viral mediators, via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. STAT1 and STAT2 have been well characterized and shown to upregulate IFN-stimulated gene (ISG) expression; but while STAT3 is also activated by IFN-alpha, its role in anti-viral ISG induction is unclear.

STAT3 is a member of the STAT protein family, which regulates many aspects of cell growth, survival, and differentiation. Malfunction of this signaling pathway is frequently observed in primary tumors and leads to increased angiogenesis and enhanced tumor survival. Knockout studies have provided evidence that STAT proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance. Constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis. It has anti-apoptotic as well as proliferative effects. Several viruses, including hepatitis C and mumps, reduce cellular STAT3 protein levels, via the promotion of ubiquitin-mediated proteasomal degradation. This viral immune evasion mechanism suggests an undiscovered anti-viral role for STAT3 in IFN-alpha signaling.

To investigate STAT3’s functional involvement in the Type I IFN pathway, investigators at Trinity College Dublin first analyzed its effect on the replication of two viruses, influenza and vaccinia. Viral plaque assays, using mouse wild type embryonic fibroblasts (MEFs) and MEFs that lacked STAT3, revealed that STAT3 was required for the inhibition of influenza and vaccinia replication. Furthermore, blocking STAT3 by short hairpin RNA (shRNA) inhibition also enhanced influenza replication and hindered induction of several, well characterized, anti-viral ISGs.

Senior author Dr. Nigel Stevenson, assistant professor of immunology at Trinity College Dublin, said, "For decades we have known that STAT3 is essential for healthy cell growth, but our new revelation identifies it for the first time as an essential anti-viral component in the interferon signaling pathway. In fact, we found that without STAT3, cells cannot fight the common flu virus or the pox vaccinia virus. We thought that since the interferon signaling pathway enhances the immune response against viruses so effectively, viruses might have evolved means to block it - such a reality would explain why several viruses are so troublesome to defeat."

"Of course a major goal of our ongoing work is to find solutions to the real-world problems faced by the thousands of people who cannot clear certain viruses after they have been infected," said Dr. Stevenson. "This discovery opens the door to new therapeutic options, which, we hope, will be able to help people restore their natural immunity against a host of problematic viruses."

The study was published in the December 17, 2016, online edition of the journal Cellular and Molecular Life Sciences.