Glycolysis regulates KRAS plasma membrane localization and function through defined glycosphingolipids

KRAS is a small GTPase that regulates cell proliferation. Here, the authors show that a subset of cell surface glycosphingolipids regulate KRAS plasma membrane localization by modulating inner leaflet lipid composition, uncovering a requirement for KRAS oncogenesis that may have therapeutic potential. Oncogenic KRAS expression generates a metabolic dependency on aerobic glycolysis, known as the Warburg effect. We report an effect of increased glycolytic flux that feeds into glycosphingolipid biosynthesis and is directly linked to KRAS oncogenic function. High resolution imaging and genetic approaches show that a defined subset of outer leaflet glycosphingolipids, including GM3 and SM4, is required to maintain KRAS plasma membrane localization, with GM3 engaging in cross-bilayer coupling to maintain inner leaflet phosphatidylserine content. Thus, glycolysis is critical for KRAS plasma membrane localization and nanoscale spatial organization. Reciprocally oncogenic KRAS selectively upregulates cellular content of these same glycosphingolipids, whose depletion in turn abrogates KRAS oncogenesis in pancreatic cancer models. Our findings expand the role of the Warburg effect beyond ATP generation and biomass building to high-level regulation of KRAS function. The positive feedforward loop between oncogenic KRAS signaling and glycosphingolipid synthesis represents a vulnerability with therapeutic potential.

Automated summary

The authors demonstrate that a specific subset of cell surface glycosphingolipids regulates the localization of KRAS protein on the plasma membrane, highlighting a potential therapeutic target for KRAS-driven oncogenesis. They show that oncogenic KRAS expression increases the reliance on aerobic glycolysis and affects the synthesis of glycosphingolipids, which in turn is critical for the localization and organization of KRAS on the plasma membrane. Depletion of these glycosphingolipids diminishes the oncogenic function of KRAS in pancreatic cancer models. This study expands the understanding of the Warburg effect and reveals a potential vulnerability with therapeutic implications.