INVESTIGADORES
MARTINEZ CALEJMAN Camila
congresos y reuniones científicas
Título:
mTORC2 stimulates acetyl-CoA synthesis and DNL by dually controlling ACLY and ACSS2
Autor/es:
MARTINEZ CALEJMAN, C.; LI, HUAWEI; GUERTIN, DAVID
Lugar:
Snowbird
Reunión:
Congreso; Keystone Symposia-Tumor Metabolism; 2018
Institución organizadora:
Keystone Symposia
Resumen:
The mechanistic target of rapamycin (mTOR) kinase is a master regulator of growth that assembles into two different complexes called mTORC1 and mTORC2. Previous work has shown that mTORC2 is required for the progression of several types of cancer, which is likely through its regulation of AKT. However, the function of mTORC2-dependent AKT phosphorylation is incompletely understood. Our group has previously shown that mTORC2 loss in vivo in adipocytes profoundly decreases expression of the major de novo lipogenesis (DNL) enzymes, ATP-citrate lyase (ACLY), acetyl-coA carboxylase, and fatty acid synthase as well as their transcriptional activator ChREBPβ revealing a critical role for mTORC2 in regulating DNL. However, due to the chronic nature of mTORC2 loss in vivo, it remains unclear if transcriptional attenuation of DNL is a primary or secondary effect. In this study, we investigated the mechanism by which mTORC2 acutely regulates DNL. Using an inducible deletion strategy in preadipocytes combined with phospho-proteomics and metabolomics, we identify a subset of AKT substrates that uniquely depends upon mTORC2 and includes ACLY. Consequently, acute mTORC2 loss decreases acetyl-coA levels and DNL, which impairs adipogenesis in vitro, and precedes the transcriptional silencing of DNL observed in vivo. Surprisingly, while prolonged mTORC2 loss in vivo leads to acly repression, it fails to trigger the compensatory generation of acetyl-CoA from acetate that occurs when acly is deleted, which is driven by ACSS2, thus revealing an additional role for mTORC2 in regulating the production of acetyl-coA from acetate. We conclude that a major function of mTORC2 is to stimulate anabolic acetyl-coA synthesis, which has important implications for understanding DNL, epigenetic programing, and their roles in type 2 diabetes and cancer.