Metabolic Regulation of Protein N-Alpha-Acetylation by Bcl-xL Promotes Cell Survival
Caroline H. Yi, Heling Pan, Jan Seebacher, Il-Ho Jang, Sven G. Hyberts, Gregory J. Heffron, Matthew G. Vander Heiden, Renliang Yang, Fupeng Li, Jason W. Locasale, Hadar Sharfi, Bo Zhai, Ricard Rodriguez-Mias, Harry Luithardt, Lewis C. Cantley, George Q. Daley John M. Asara, Steven P. Gygi, Gerhard Wagner, Chuan-Fa Liu and Junying Yuan
Previous experiments suggest a connection between the N-alpha-acetylation of proteins and sensitivity of cells to apoptotic signals. Here, we describe a biochemical assay to detect the acetylation status of proteins and demonstrate that protein N-alpha-acetylation is regulated by the availability of acetyl-CoA. Because the antiapoptotic protein Bcl-xL is known to influence mitochondrial metabolism, we reasoned that Bcl-xL may provide a link between protein N-alpha-acetylation and apoptosis. Indeed, Bcl-xL overexpression leads to a reduction in levels of acetyl-CoA and N-alpha-acetylated proteins in the cell. This effect is independent of Bax and Bak, the known binding partners of Bcl-xL. Increasing cellular levels of acetyl-CoA by addition of acetate or citrate restores protein N-alpha-acetylation in Bcl-xL-expressing cells and confers sensitivity to apoptotic stimuli. We propose that acetyl-CoA serves as a signaling molecule that couples apoptotic sensitivity to metabolism by regulating protein N-alpha-acetylation.