期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：28
页码：E3679-E3688
DOI：10.1073/pnas.1505995112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe small GTPase Ran plays fundamental roles in cellular processes such as nucleo-cytoplasmic transport, mitotic spindle formation, and nuclear envelope assembly. Recently, Ran was found to be lysine acetylated, among others, in functionally important regions such as switch I and switch II. Using the genetic code expansion concept we show that lysine acetylation affects many important aspects of Ran function such as RCC1-catalyzed nucleotide exchange, intrinsic nucleotide hydrolysis, import/export complex formation, and Ran subcellular localization. Finally, we present evidence for a regulation of Ran acetylation by sirtuin deacetylases and lysine acetyltransferases. Ran is a small GTP-binding protein of the Ras superfamily regulating fundamental cellular processes: nucleo-cytoplasmic transport, nuclear envelope formation and mitotic spindle assembly. An intracellular Ran[bullet]GTP/Ran[bullet]GDP gradient created by the distinct subcellular localization of its regulators RCC1 and RanGAP mediates many of its cellular effects. Recent proteomic screens identified five Ran lysine acetylation sites in human and eleven sites in mouse/rat tissues. Some of these sites are located in functionally highly important regions such as switch I and switch II. Here, we show that lysine acetylation interferes with essential aspects of Ran function: nucleotide exchange and hydrolysis, subcellular Ran localization, GTP hydrolysis, and the interaction with import and export receptors. Deacetylation activity of certain sirtuins was detected for two Ran acetylation sites in vitro. Moreover, Ran was acetylated by CBP/p300 and Tip60 in vitro and on transferase overexpression in vivo. Overall, this study addresses many important challenges of the acetylome field, which will be discussed.
