TY - JOUR
T1 - Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation
AU - Bruning, Ulrike
AU - Morales-Rodriguez, Francisco
AU - Kalucka, Joanna
AU - Goveia, Jermaine
AU - Taverna, Federico
AU - Queiroz, Karla C.S.
AU - Dubois, Charlotte
AU - Cantelmo, Anna Rita
AU - Chen, Rongyuan
AU - Loroch, Stefan
AU - Timmerman, Evy
AU - Caixeta, Vanessa
AU - Bloch, Katarzyna
AU - Conradi, Lena Christin
AU - Treps, Lucas
AU - Staes, An
AU - Gevaert, Kris
AU - Tee, Andrew
AU - Dewerchin, Mieke
AU - Semenkovich, Clay F.
AU - Impens, Francis
AU - Schilling, Birgit
AU - Verdin, Eric
AU - Swinnen, Johannes V.
AU - Meier, Jordan L.
AU - Kulkarni, Rhushikesh A.
AU - Sickmann, Albert
AU - Ghesquière, Bart
AU - Schoonjans, Luc
AU - Li, Xuri
AU - Mazzone, Massimiliano
AU - Carmeliet, Peter
N1 - Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/12/4
Y1 - 2018/12/4
N2 - The role of fatty acid synthesis in endothelial cells (ECs) remains incompletely characterized. We report that fatty acid synthase knockdown (FASN KD ) 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, FASN KD 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 FASN KD 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.
AB - The role of fatty acid synthesis in endothelial cells (ECs) remains incompletely characterized. We report that fatty acid synthase knockdown (FASN KD ) 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, FASN KD 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 FASN KD 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.
KW - angiogenesis
KW - endothelial cell
KW - fatty acid synthase
KW - lipids
KW - mTOR
KW - mTORC1
KW - malonyl-CoA
KW - metabolism
KW - post-translational modifications
KW - protein malonylation
UR - https://www.scopus.com/pages/publications/85059307725
U2 - 10.1016/j.cmet.2018.07.019
DO - 10.1016/j.cmet.2018.07.019
M3 - Article
C2 - 30146486
AN - SCOPUS:85059307725
SN - 1550-4131
VL - 28
SP - 866-880.e15
JO - Cell metabolism
JF - Cell metabolism
IS - 6
ER -