Sci. STKE, 16 October 2007
Cytokines Phosphorylation Isnt 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]
Citation: E. M. Adler, Phosphorylation Isnt Everything. Sci. STKE 2007, tw369 (2007).
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