An Acylation Cycle Regulates Localization and Activity of Palmitoylated Ras Isoforms

TLDR

Depalmitoylation releases farnesylated Ras to all membranes, after which repalmitoylation traps it at the Golgi and the secretory pathway shuttles it to the plasma membrane. The constitutive de/reacylation cycle drives Ras between the plasma membrane and Golgi, preventing nonspecific endomembrane residence, initiating Golgi‑localized activation, and producing isoform‑specific growth‑factor responses.

Abstract

We show that the specific subcellular distribution of H- and Nras guanosine triphosphate–binding proteins is generated by a constitutive de/reacylation cycle that operates on palmitoylated proteins, driving their rapid exchange between the plasma membrane (PM) and the Golgi apparatus. Depalmitoylation redistributes farnesylated Ras in all membranes, followed by repalmitoylation and trapping of Ras at the Golgi, from where it is redirected to the PM via the secretory pathway. This continuous cycle prevents Ras from nonspecific residence on endomembranes, thereby maintaining the specific intracellular compartmentalization. The de/reacylation cycle also initiates Ras activation at the Golgi by transport of PM-localized Ras guanosine triphosphate. Different de/repalmitoylation kinetics account for isoform-specific activation responses to growth factors.