Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation
2 VIB-KU Leuven | CCB - VIB-KU Leuven Center for Cancer Biology
3 LKI - Leuven Cancer Institute [Leuven, Belgium]
4 VIB-CCB - Laboratory of Angiogenesis and Vascular Metabolism [Leuven, Belgium]
5 Aarhus University [Aarhus]
6 SYSU - Sun Yat-sen University [Guangzhou]
7 ISAS - Leibniz-Institut für Analytische Wissenschaften
8 VIB-UGent | CMB - VIB-UGent Center for Medical Biotechnology
9 UGent - Universiteit Gent = Ghent University = Université de Gand
10 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
11 VIB - Vlaams Instituut voor Biotechnologie = Flanders Institute for Biotechnology [Ghent]
12 Cardiff University
13 WSU - Washington State University
14 VIB Proteomics Core [Ghent]
15 Buck Institute for Research on Aging
16 National Cancer Institute Frederick
17 University of Aberdeen
18 RUB - Ruhr University Bochum = Ruhr-Universität Bochum [Bochum]
19 VIB-KU Leuven | CFM - VIB-KU Leuven Center for Microbiology
- Fonction : Auteur
- PersonId : 1432844
- IdHAL : lucas-treps
- ORCID : 0000-0003-0735-9000
- Fonction : Auteur
- PersonId : 745108
- IdHAL : eric-verdin
- ORCID : 0000-0002-6416-1597
- Fonction : Auteur
- PersonId : 1563950
Résumé
The role of fatty acid synthesis in endothelial cells (ECs) remains incompletely characterized. We report that fatty acid synthase knockdown (FASNKD) in ECs impedes vessel sprouting by reducing proliferation. Endothelial loss of FASN impaired angiogenesis in vivo, while FASN blockade reduced pathological ocular neovascularization, at >10-fold lower doses than used for anti-cancer treatment. Impaired angiogenesis was not due to energy stress, redox imbalance, or palmitate depletion. Rather, FASNKD elevated malonyl-CoA levels, causing malonylation (a post-translational modification) of mTOR at lysine 1218 (K1218). mTOR K-1218 malonylation impaired mTOR complex 1 (mTORC1) kinase activity, thereby reducing phosphorylation of downstream targets (p70S6K/4EBP1). Silencing acetyl-CoA carboxylase 1 (an enzyme producing malonyl-CoA) normalized malonyl-CoA levels and reactivated mTOR in FASNKD ECs. Mutagenesis unveiled the importance of mTOR K1218 malonylation for angiogenesis. This study unveils a novel role of FASN in metabolite signaling that contributes to explaining the anti-angiogenic effect of FASN blockade.