Acetylation of sphingosine kinase 1 regulates cell growth and cell-cycle progression.
Sphingosine kinase 1 (SPK1) is a key enzyme in the sphingolipid metabolic pathway. It forms an essential checkpoint to regulate the relative levels of bioactive sphingolipid metabolites, ceramide, sphingosine, and sphingosine 1-phosphate (S1P). Here, we present evidence that SPK1 is acetylated by the intrinsic acetyltransferase activity of p300/cAMP-response element-binding protein (CREB)-binding protein (CBP) at a conserved acetylation motif (the GK motif). This post-translational modification may be an important regulator of SPK1 protein, as acetylation by p300 or CBP increased its stability. Mutation of two lysine (K) residues in its GK motif to either arginine (R) or glutamine (Q) blocked SPK1 ubiquitination and prevented its degradation by the proteasome. The processes of acetylation and ubiquitination may compete for the same lysine residues and, therefore, form a switch for SPK1 protein regulation. Intriguingly, human embryonic kidney (HEK) 293 cells stably expressed the mutated form of SPK1, in which the K residue was mutated to Q (Q-SPK1), and this mutated form mimicked acetylated SPK1. These cells were larger in size and had a slower growth rate compared to cells that expressed wild-type SPK1 (W-SPK1) or the K/R-mutated SPK1 (R-SPK1). These data suggest that SPK1 acetylation plays a key role in cell growth, cell size, and cell-cycle control.
School of Chemical Engineering and Technology, Tianjin University, Tianjin, China.
Hongyang
H
Yu
Yong
Y
Shao
Lihua
L
Gao
Liancheng
L
Zhang
Kanghe
K
Guo
Chutse
C
Wu
Xianwen
X
Hu
Haifeng
H
Duan
D000107:Acetylation; D000595:Amino Acid Sequence; D002453:Cell Cycle; D049109:Cell Proliferation; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D058977:Molecular Sequence Annotation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D000099157:Sphingosine Kinase
D008239:Lysine; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase