Editors' ChoiceCytokines

Phosphorylation Isn’t Everything

Science's STKE  16 Oct 2007:
Vol. 2007, Issue 408, pp. tw369
DOI: 10.1126/stke.4082007tw369

Interferon-α (IFN-α) binds to its receptors (IFNαR1 and IFNαR2), stimulating their heterodimerization and the activation of receptor-associated tyrosine kinases. IFN-α 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 regulatoryfactor 9 (IRF9) to form the interferon-stimulated gene factor 3 (ISGF3) complex, which translocates to the nucleus to activate target genes. Noting that IFN-α 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-α signaling. IFN-α 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 IFNαR2. Mutational analysis indicated that CBP bound to a region between IFNαR2 Gly335 and Ser392 and that phosphorylation of two serines within this region stabilized the interaction. IFN-α elicited IFNαR2 acetylation, which was abolished by siRNA knockdown of CBP, and a combination of mutational and mass spectrometry analysis indicated that acetylation took place on IFNαR2 Lys399. IRF9 associated with IFNαR2 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 IFNαR2, IRF9, and STAT2 were required for IFN-α-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]