Cytokines Phosphorylation Isn’t Everything

Elizabeth M. Adler

Science's STKE, AAAS, Washington, DC 20005, USA

Interferon- (IFN-) binds to its receptors (IFNR1 and IFNR2), stimulating their heterodimerization and the activation of receptor-associated tyrosine kinases. IFN- receptor phosphorylation enables the recruitment and activation of signal transducer and activator of transcription 2 (STAT2) and the consequent recruitment and activation of STAT1. STAT1 and STAT2 heterodimerize with interferon regulatory factor 9 (IRF9) to form the interferon-stimulated gene factor 3 (ISGF3) complex, which translocates to the nucleus to activate target genes. Noting that IFN- stimulates the interaction of STAT2 with the histone acetyltransferase transcriptional coactivator CREB-binding protein (CBP), Tang et al. investigated the role of acetylation in IFN- signaling. IFN- treatment led to an increase in cytoplasmic CBP in HeLa and other cells, concurrent with a decrease in nuclear CBP, and promoted the coimmunoprecipitation of CBP with IFNR2. Mutational analysis indicated that CBP bound to a region between IFNR2 Gly³³⁵ and Ser³⁹² and that phosphorylation of two serines within this region stabilized the interaction. IFN- elicited IFNR2 acetylation, which was abolished by siRNA knockdown of CBP, and a combination of mutational and mass spectrometry analysis indicated that acetylation took place on IFNR2 Lys³⁹⁹. IRF9 associated with IFNR2 through Lys³⁹⁹ and was itself acetylated by CBP, as were STAT2 and STAT1, and CBP overexpression stimulated ISGF3-dependent transcriptional activity, whereas siRNA directed against CBP inhibited it. Moreover, CBP-mediated acetylation of IFNR2, IRF9, and STAT2 were required for IFN--dependent association of ISGF3 with chromatin and antiviral activity. Thus, the authors conclude that acetylation--as well as phosphorylation--plays a key role in type I interferon receptor signaling.

X. Tang, J.-S. Gao, Y.-j. Guan, K. E. McLane, Z.-L. Yuan, B. Ramratnam, Y. E. Chin, Acetylation-dependent signal transduction for type I interferon receptor. Cell 131, 93-105 (2007). [PubMed]

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