Signal transducer and activator of transcription (STAT) proteins are latent in the cytoplasm until extracellular signals — such as cytokines or growth factors — induce their activation, dimerization and translocation to the nucleus. Here, the STAT dimers bind to DNA and promote the transcription of various genes. In response to the extracellular signals, STATs are phosphorylated and this post-translational modification is thought to be necessary for STAT activation. However, as unphosphorylated STATs can still dimerize and induce transcription, Chin and colleagues investigated whether other modifications might be important for STAT activation, and they report their results in Science.

Proteins of the cAMP-response-element-binding protein (CREB)-binding protein (CBP)/p300 family have intrinsic histone-acetylase activity, and they are known to associate with various STATs and promote STAT-mediated transcription. So, the authors looked at whether STATs can be acetylated, and found that STAT3 acetylation was induced by treating cells with extracellular signalling proteins. In addition, they showed that this acetylation was increased by transfecting cells with CBP or p300, and that neither STAT3 phosphorylation, nor the activity of the Src-homology-2 domain of STAT3, were required for this modification.

A broad inhibitor of histone deacetylases (HDACs) increased STAT3 acetylation in response to p300 transfection or cytokine treatment, and Chin and co-workers found that STAT3 deacetylation could be mediated by type-I HDACs. It therefore seems that p300 and type-I HDACs, which are present in most cell types, might control cytokine-induced STAT3 acetylation/deacetylation.

Next, the authors showed that Lys685 of STAT3, which is conserved in several STATs from various species, was acetylated by p300, and they investigated the effect of this modification on STAT3 activity. They showed that the dimerization of wild-type STAT3 was stabilized by cytokine treatment and that, by contrast, no dimerization could be detected for Lys685Arg-mutant STAT3 proteins after cytokine treatment, even though these mutant proteins were phosphorylated. Lys685 acetylation therefore seems to be important for STAT3 dimerization. Furthermore, the authors showed that cytokine treatment could induce the formation of complexes between DNA and wild-type STAT3, but not DNA and Lys685Arg STAT3.

In the final part of their study, Chin and colleagues looked at the effect of STAT3 acetylation on cell growth in vivo, as STAT3 regulates several cell-growth- and cell-survival-related genes. In a cell line that lacks STAT3, the expression level of three such genes was low, with or without cytokine treatment, but, after cytokine treatment, cells that had been transfected with wild-type STAT3 — but not Lys685Arg STAT3 — showed increased expression of these genes. They also showed that wild-type, but not Lys685Arg, STAT3 could promote cell-cycle progression and cell growth in response to cytokines.

So, this work indicates that STAT acetylation is necessary for the stable dimerization of STATs and for them to activate transcription. Furthermore, as CBP/p300 is known to associate with various STATs, “...it is possible that all STAT family members are tightly regulated by the acetylation and deacetylation cycle.”