Tumor Suppressor p14ARF Enhances IFN-γ-Activated Immune Response by Inhibiting PIAS1 via SUMOylation

The Journal of Immunology : Official Journal of the American Association of Immunologists
Jennifer AlaguKoji Itahana

Abstract

The ability of cells to induce the appropriate transcriptional response to inflammatory stimuli is crucial for the timely induction of host defense mechanisms. Although a role for tumor suppressor p14ARF (ARF) in the innate immune response was previously demonstrated, the underlying mechanism is still unclear. ARF is a potent upregulator of protein SUMOylation; however, no association of this function with the immune system has been made. In this study, we show the unique role of ARF in IFN-γ-induced immune response using human cell lines. Through a systematic search of proteins SUMOylated by ARF, we identified PIAS1, an inhibitor of IFN-activated transcription factor STAT1, as a novel ARF-binding partner and SUMOylation target. In response to IFN-γ treatment, ARF promoted PIAS1 SUMOylation to inhibit the ability of PIAS1 to attenuate IFN-γ response. Wild-type, but not ARF mutants unable to enhance PIAS1 SUMOylation, prevented the PIAS1-mediated inhibition of IFN-γ response. Conversely, the SUMO-deconjugase SENP1 deSUMOylated PIAS1 to reactivate PIAS1 that was inhibited by ARF. These findings suggest that PIAS1 function is negatively modulated by SUMO modification and that SUMOylation by ARF is required to inhibit PIAS1 activit...Continue Reading

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Citations

Apr 8, 2020·The FEBS Journal·Arda B Celen, Umut Sahin
Mar 27, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Zhi ZhangFanhong Zeng
May 18, 2021·Expert Review of Vaccines·Burcu Temizoz, Ken J Ishii

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