SIRT2 and Lysine Fatty Acylation Regulate the Activity of RalB and Cell Migration.

Abstract

Protein lysine fatty acylation is increasingly recognized as a prevalent and important protein post-translation modification. Recently, it has been shown that K-Ras4a, R-Ras2, and Rac1 are regulated by lysine fatty acylation. Here, we investigated whether other members of the Ras superfamily could also be regulated by lysine fatty acylation. Several small GTPases exhibit hydroxylamine resistant fatty acylation, suggesting they may also have protein lysine fatty acylation. We further characterized one of these GTPases, RalB. We show that RalB has C-terminal lysine fatty acylation, with the predominant modification site being Lys200. The lysine acylation of RalB is regulated by SIRT2, a member of the sirtuin family of nicotinamide adenine dinucleotide (NAD)-dependent protein lysine deacylases. Lysine fatty acylated RalB exhibited enhanced plasma membrane localization and recruited its known effectors Sec5 and Exo84, members of the exocyst complex, to the plasma membrane. RalB lysine fatty acylation did not affect the proliferation or anchorage-independent growth but did affect the trans-well migration of A549 lung cancer cells. This study thus identified an additional function for protein lysine fatty acylation and the deacylase SIRT2.