NOVEL ROLE OF FATTY ACID SYNTHASE IN ANGIOGENESIS THROUGH MODULATION OF LYSINE MALONYLATION OF MTOR

ABSTRACT: The role of fatty acid synthesis (FAS) in endothelial cells (ECs) remains incompletely characterized. In this project, we found that silencing of fatty acid synthase (FASN) impedes vessel sprouting by reducing EC proliferation. Moreover, loss of FASN in ECs impaired angiogenesis in vivo, and FASN blockade reduced pathological ocular neovascularization. FASN silencing increased malonyl-CoA levels and immunoblotting of EC lysates for malonylated lysine residues (Kmal) revealed that this led to increased levels of protein malonylation. To identify the nature of some of the malonylated proteins we performed a proteomics screen using an anti-Kmal antibody to enrich Kmal peptides from a tryptic digest of EC lysates, and then analyzed Kmal peptides by LC-MS/MS. In proteomics analysis, we identified malonylation of mTOR at lysine 1218, a poorly characterized post-translational modification. Malonylation of mTOR did not compromise the mTORC1 complex stability or lysosomal membrane localization, but reduced the kinase activity of the complex.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Endothelial Cell

SUBMITTER: Evy Timmerman  

LAB HEAD: Carmeliet Peter

PROVIDER: PXD006503 | Pride | 2019-07-08

REPOSITORIES: Pride