Anti-SIRT4 (aa 302-314) polyclonal antibody

Proliferating mammalian cells use glutamine as a source of nitrogen and as a key anaplerotic source to provide metabolites to the tricarboxylic acid cycle (TCA) for biosynthesis. Recently, mammalian target of rapamycin complex 1 (mTORC1) activation has been correlated with increased nutrient uptake and metabolism, but no molecular connection to glutaminolysis has been reported. Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). Thus, a relationship between mTORC1, SIRT4, and cancer is suggested by our findings. Indeed, SIRT4 expression is reduced in human cancer, and its overexpression reduces cell proliferation, transformation, and tumor development. Finally, our data indicate that targeting nutrient metabolism in energy-addicted cancers with high nnTORC1 signaling may be an effective therapeutic approach.

Recently the function of the sirtuin family, named after their homology to the Saccharomyces cerevisiae gene silent information regulator 2 (Sir2), has received a lot of attention, as their beneficial impact on longevity was linked to their effects on metabolic control. All sirtuins require nicotinamide adenine dinucleotide (NAD(+)) for their deacetylase or ADP-ribosyl transferase activity, linking their function tightly to cellular energy levels. SIRT1, the founding member of the sirtuin family, modulates many aspects of glucose and lipid homeostasis in almost all key metabolic tissues. Other members including SIRT2, SIRT3, and SIRT4 are also implicated in various metabolic processes. Here, we review the recent data related to the role of sirtuins in the control of metabolic homeostasis and possible underlying molecular mechanisms.