ID: 22: Reduction by SUMO of interferon gamma, but not alpha, transcriptional response

Interferons (IFNs) orchestrate immune defense through induction of hundred of genes. Small ubiquitin-like modifier (SUMO) is involved in various cellular functions, but little is known about its role on IFN responses. Prior work identified SUMOylation of STAT1 as an important mode of regulation of IFN γ signaling. Here, we investigated the various roles of SUMO in IFN signaling, transcriptional response and IFN-induced biological effects. We first show that SUMO overexpression leads to STAT1 SUMOylation and to a decrease in IFN-induced STAT1 phosphorylation. This process correlates with lower levels of STAT1 binding to GAS in response to IFN γ , while the binding of an ISGF3-like complex to ISRE in response to IFN α is not altered. Interestingly, IFNs exert a negative retro-control on their own signaling by enhancing STAT1 SUMOylation. Furthermore, we show that expression of each SUMO paralog selectively inhibits IFN γ -induced IP-10 and TAP1 mRNA expression. Importantly, inhibition of IFN γ signaling by SUMO is associated with a decrease of IFN γ -induced apoptosis and cell growth inhibition as well as a dramatic reduction of IP-10-induced chemotaxis. Conversely, inhibition of SUMOylation results in a higher IFN γ -induced STAT1 phosphorylation and biological responses. In conclusion, our work thus allows the inclusion of SUMO to the list of negative regulators of IFN signaling known to date and posits SUMO as a possible contributor to IFN γ resistance.