Volume 21, Issue 2, June 2005

Table of Contents 21-2

Regulation of Stat3 Dimerization

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Signal transducers and activators of transcriptions (STAT/Stat) are a family of intracellular proteins that transmit the messages of cytokines (including human growth hormone [hGH]) to the nucleus after interaction of ligands with their respective cell membrane receptors; there Stats serve as transcription factors.¹ In order to function, the Stats are phosphorylated, transported into the nucleus, dimerized, and bound to the response elements of targeted genes that enable the cell to react to the cytokine’s instructions. Yuan and colleagues demonstrated that acetylation of lysine⁶⁸⁵ of Stat3 after cytokine stimulation is essential for Stat3-mediated gene transcription. First, they showed that exposure to the cytokines oncostatin M and interferon-α led to acetylation of cytoplasmic Stat3 in cells in vitro. This process was mediated by proteins with histone acyltransferase (HAT) activity and suppressed by inhibitors of this enzyme. Acetylation was not dependent upon Stat3 phosphorylation. Non-acylated Stat3 did not have transcription-activating ability. The lysine residue acylated by Stat3 was demonstrated to be amino acid number 685 by examination of different segments of this protein and by the observation that substitution of arginine for leucine position 685 did not lead to acetylation of other lysine residues in Stat3. Lysine⁶⁸⁵ is found between an SH2 domain (a segment of 30-40 conserved amino acids) and the transcription-activating domain of Stat3. Acetylation of lysine⁶⁸⁵ was not required for phosphorylation of Stat3, nor for its translocation into the nucleus, but homodimerization, DNA binding, and consequently activation of transcription were impaired when it was not acylated. Furthermore, acetylation of lysine⁶⁸⁵ was necessary for transcription of cell growth regulatory genes such as cyclin D1 and for cell growth. The investigators concluded that site-specific acetylation of a leucine residue of Stat3 (and likely of other STAT proteins as well as other transcription factors) is essential for its transcription regulating function.

Yuan ZL, Guan YJ, Chatterjee D, Chin YE. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science. 2005;307:269–273.

Editor’s Comment: The clinical significance of intracellular signal transduction pathways in endocrine disorders is becoming increasingly apparent. Thus, the importance of STAT5b in the cellular response to hGH has been dramatically demonstrated by the report of a child with growth retardation and subnormal responsiveness to hGH due to a loss-of-function mutation in the gene encoding this protein.² Clearly, the post-translational modifications that take place in the endoplasmic reticulum and Golgi apparatus by alterations in amino acid composition of the gene product (proteolysis of signal peptides and pro-protein sequences) and in 3-dimensional structures that take place in part by phosphorylation, methylation, sumoylation, and ubiquitination play key roles in the functionality of the encoded protein. To this list of post-translational modifications may now be added acetylation of the STAT proteins. It is only a matter of time until an “accident of nature” permits identification of additional patients with impaired growth due to one or more of these post-translational processes. It is also possible that polymorphic variants in the STAT proteins and their post-translational modifications that transmit the hGH signal “more or less well” may underlie some of the “genetic” variation in height of normal populations. However, as O’Shea et al¹ point out, the work of Yuan et al is open to alternative interpretations and, therefore, must be confirmed by other investigators.