The transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis

Abstract

Biological systems to sense and respond to metabolic perturbations are critical for the maintenance of cellular homeostasis. Here we describe a hepatic system in this context orchestrated by the transcriptional corepressor C-terminal binding protein 2 (CtBP2) that harbors metabolite-sensing capabilities. The repressor activity of CtBP2 is reciprocally regulated by NADH and acyl-CoAs. CtBP2 represses Forkhead box O1 (FoxO1)-mediated hepatic gluconeogenesis directly as well as Sterol Regulatory Element-Binding Protein 1 (SREBP1)-mediated lipogenesis indirectly. The activity of CtBP2 is markedly defective in obese liver reflecting the metabolic perturbations. Thus, liver-specific CtBP2 deletion promotes hepatic gluconeogenesis and accelerates the progression of steatohepatitis. Conversely, activation of CtBP2 ameliorates diabetes and hepatic steatosis in obesity. The structure-function relationships revealed in this study identify a critical structural domain called Rossmann fold, a metabolite-sensing pocket, that is susceptible to metabolic liabilities and potentially targetable for developing therapeutic approaches.

Master corepressor inactivation through multivalent SLiM-induced polymerization mediated by the oncogene suppressor RAI2

“…This inactivation mechanism complements its proven loss of activity in the absence of NAD + /NADH, which is required for CtBP tetrameric assembly and the potential induction of its metabolic-and redox-sensing properties (Fig. 6) [41][42][43][44] PxDLS protein targets does not require oligomerization 22,45 , CtBP tetramerization has been proposed as a prerequisite for simultaneous recruitment of multiple chromatin-modifying enzymes and/or proper nuclear localization 19,26 .…”

Oncogene EVI1 Drives Acute Myeloid Leukemia Via a Targetable Interaction with CTBP2

“…CTBP1 and CTBP2 are highly structured proteins that contain two large oxireductase enzymatic domains (44). Both are annotated as catalysts of a NAD+ to NADPH conversion in the methionine salvage pathway, even though this has been studied mostly for CTBP1 (45)(46)(47). NAD binding has been reported to be important for homo-or heterodimerization of CTBPs with each other (48).…”

ZBTB18 inhibits SREBP-dependent lipid synthesis by halting CTBPs and LSD1 activity in glioblastoma

“…Recently, CTBP2 has been linked to the inhibition of cholesterol synthesis in breast cancer cells through direct repression of SREBF2 expression ( Zhao et al, 2019 ). Furthermore, CTBP2 was shown to repress fatty acid biosynthesis in the liver ( Sekiya et al, 2021 ). Although apparently in contrast to our proposed role of CTBP2 as an activator of SREBP genes, it is possible that CTBP function might change based on the interaction with other transcription factors.…”

“…According to this possibility, CTBP2 repression of fatty acid in breast cancer requires the interaction with the transcriptional repressor ZEB1, which was never detected as a CTBP2 partner in our co-immunoprecipitation analysis in GBM cells. Instead, the study performed by Sekiya et al (2021) proposes that CTBP2 interacts with the SREBF1 protein to directly inhibit its transcriptional activity. However, these proposed models are mechanistically different from the one reported in our study, in which the newly described CTBP function seems to depend on the activating role of LSD1.…”