GOLGA7 is essential for NRAS trafficking from the Golgi to the plasma membrane but not for its palmitoylation

Abstract

NRAS mutations are most frequently observed in hematological malignancies and are also common in some solid tumors such as melanoma and colon cancer. Despite its pivotal role in oncogenesis, no effective therapies targeting NRAS has been developed. Targeting NRAS localization to the plasma membrane (PM) is a promising strategy for cancer therapy, as its signaling requires PM localization. However, the process governing NRAS translocation from the Golgi apparatus to the PM after lipid modification remains elusive. This study identifies GOLGA7 as a crucial factor controlling NRAS' PM translocation, demonstrating that its depletion blocks NRAS, but not HRAS, KRAS4A and KRAS4B, translocating to PM. GOLGA7 is known to stabilize the palmitoyltransferase ZDHHC9 for NRAS and HRAS palmitoylation, but we found that GOLGA7 depletion does not affect NRAS' palmitoylation level. Further studies show that loss of GOLGA7 disrupts NRAS anterograde trafficking, leading to its cis-Golgi accumulation. Remarkably, depleting GOLGA7 effectively inhibits cell proliferation in multiple NRAS-mutant cancer cell lines and attenuates NRAS^G12D-induced oncogenic transformation in vivo. These findings elucidate a specific intracellular trafficking route for NRAS under GOLGA7 regulation, highlighting GOLGA7 as a promising therapeutic target for NRAS-driven cancers.