Lipid acyl chain remodeling governs KRAS nanoclustering and oncogenic functions through membrane composition control
- 1University of Texas Health Science Center Houston
Abstract
KRAS signaling is spatially organized within the dynamic proteolipid nanoclusters on the plasma membrane (PM) that selectively concentrate anionic phospholipids, yet the molecular determinants governing this lipid sorting remain incompletely defined. Here we identify phospholipid acyl chain composition as a critical regulator of KRAS spatial organization and signal output. Using genetic and pharmacological perturbation of lysophosphatidylcholine acyltransferase 3 (LPCAT3), a key enzyme that incorporates polyunsaturated fatty acids into phospholipids, we demonstrate that remodeling of membrane acyl chain unsaturation alters the phosphatidylserine (PS) lipidome without changing total PS abundance. Loss of LPCAT3 depletes polyunsaturated PS species, disrupts KRAS PM association and nanoclustering, and attenuates downstream MAPK signaling and oncogenic activity across multiple KRAS mutant contexts. Acute restoration of polyunsaturated, but not saturated, lipids rescue KRAS nanoclustering, establishing a direct requirement for lipid unsaturation in sustaining signaling-competent assemblies. Mechanistically, these findings define membrane acyl chain composition as a determinant of proteolipid organization that encodes KRAS signaling capacity. Consistent with this model, LPCAT3 inhibition selectively impairs KRAS-dependent proliferation and sensitizes tumor cells to direct KRAS inhibition. Together, this work uncovers lipid acyl chain remodeling as a fundamental regulator of membrane-associated signaling and identifies membrane composition as an exploitable vulnerability in oncogenic KRAS systems.
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BibTeX
@misc{arora2026lipid,
title = {{Lipid acyl chain remodeling governs KRAS nanoclustering and oncogenic functions through membrane composition control}},
author = {N. Arora and R. Bravo and H. Liang and J. Chang and A. Reed and J. Liu and B. Cravatt and H. Ying and C. Pedroza and Y. Zhou},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.06.757084},
url = {https://www.biorxiv.org/content/10.64898/2026.10.06.757084v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Lipid acyl chain remodeling governs KRAS nanoclustering and oncogenic functions through membrane composition control
AU - N. Arora
AU - R. Bravo
AU - H. Liang
AU - J. Chang
AU - A. Reed
AU - J. Liu
AU - B. Cravatt
AU - H. Ying
AU - C. Pedroza
AU - Y. Zhou
PY - 2026
DA - 2026/10/06
PB - bioRxiv
DO - 10.64898/2026.10.06.757084
UR - https://www.biorxiv.org/content/10.64898/2026.10.06.757084v1
AB - KRAS signaling is spatially organized within the dynamic proteolipid nanoclusters on the plasma membrane (PM) that selectively concentrate anionic phospholipids, yet the molecular determinants governing this lipid sorting remain incompletely defined. Here we identify phospholipid acyl chain composition as a critical regulator of KRAS spatial organization and signal output. Using genetic and pharmacological perturbation of lysophosphatidylcholine acyltransferase 3 (LPCAT3), a key enzyme that incorporates polyunsaturated fatty acids into phospholipids, we demonstrate that remodeling of membrane acyl chain unsaturation alters the phosphatidylserine (PS) lipidome without changing total PS abundance. Loss of LPCAT3 depletes polyunsaturated PS species, disrupts KRAS PM association and nanoclustering, and attenuates downstream MAPK signaling and oncogenic activity across multiple KRAS mutant contexts. Acute restoration of polyunsaturated, but not saturated, lipids rescue KRAS nanoclustering, establishing a direct requirement for lipid unsaturation in sustaining signaling-competent assemblies. Mechanistically, these findings define membrane acyl chain composition as a determinant of proteolipid organization that encodes KRAS signaling capacity. Consistent with this model, LPCAT3 inhibition selectively impairs KRAS-dependent proliferation and sensitizes tumor cells to direct KRAS inhibition. Together, this work uncovers lipid acyl chain remodeling as a fundamental regulator of membrane-associated signaling and identifies membrane composition as an exploitable vulnerability in oncogenic KRAS systems.
ER -