Transcriptional coregulators: fine-tuning metabolism

Abstract

Metabolic homeostasis requires that cellular energy levels are adapted to environmental cues. This adaptation is largely regulated at the transcriptional level, through the interaction between transcription factors, coregulators, and the basal transcriptional machinery. Coregulators, which function as both metabolic sensors and transcriptional effectors, are ideally positioned to synchronize metabolic pathways to environmental stimuli. The balance between inhibitory actions of corepressors and stimulatory effects of coactivators enables the fine-tuning of metabolic processes. This tight regulation opens therapeutic opportunities to manage metabolic dysfunction by directing the activity of cofactors toward specific transcription factors, pathways, or cells/tissues, thereby restoring whole-body metabolic homeostasis.

Figure 1. Metabolic coregulator protein families

A representative domain structure of the Pfam-annotated domains is shown for each major protein family discussed in this review. Each color corresponds to one protein family, and differences in shading indicate distinct domains within the same structure. Domain structures are based on the human protein. HLH, Basic helix-loop-helix; PAS, (Per, Arnt, Sim) domain; SRC1, Steroid receptor coactivator; Nuc Rec Co-act, Nuclear receptor coactivator; SANT, SANT (Swi3, Ada2, N-CoR, and TFIIIB) domain, which contains the DAD or Deacetylase Activating Domain; RID, Nuclear Receptor interaction domain; RD, Repressive Domain; PCAF N, PCAF (P300/CBP-associated factor) N-terminal domain; Acetyl transf, Acetyltransferase; Hist deacetyl, Histone deacetylase; HDAC4 Gln, Glutamine rich N terminal domain of histone deacetylase 4; Arb2, Arb2 domain; TORC N, Transducer of regulated CREB activity, N terminus; TORC M, Transducer of regulated CREB activity middle domain; TORC C, Transducer of regulated CREB activity, C terminus; TFIIB, Transcription factor TFIIB repeat; RB A, Retinoblastoma-associated protein A domain; RB B, Retinoblastoma-associated protein B domain; RB C, Rb C-terminal domain; MED1, Mediator of RNA polymerase II transcription subunit 1; CPD1, Cdc4 phosphodegron 1; CPD2, Cdc4 phosphodegron 2; DAC, deacetylase catalytic domain.

Figure 2. Tissue-specific roles of NCoR1

A. NCoR1 depletion in WAT enhances the activity of the unphosphorylated form of PPARγ, which enhances adipogenesis and insulin sensitivity and reduces inflammation. In 3T3-L1 preadipocytes, the ubiquitin ligase Siah2 targets NCoR1 for proteasomal degradation, promoting the expression of CREB-dependent mitochondrial genes. B. In muscle, NCoR1 activity is reduced under conditions where fatty acid oxidation (FAO) is required. Genetic deletion of NCoR1 in the skeletal muscle enhances exercise endurance through the dereperession of PPARβ/δ, ERRs and MEF2. C. mTORC1 activation in liver during feeding, modifies the interaction of S6K2 with NCoR1 and promotes its relocalization in the nucleus, leading to the silencing of the ketogenic target genes of PPARá. Specific genetic disruption of the NCoR1-HDAC3 interaction results in alterations in diurnal gene expression controlled by REV-ERB. D. Macrophage-specific NCoR1 mutation reduces inflammation through a selective derepression of the liver X receptor (LXR).

Figure 3. Energy levels control AMPK, PKA, SIRT1 and PGC-1α–o govern mitochondrial metabolism

In times of energy depletion, such as during caloric restriction or exercise, energy stress is sensed and transduced by the AMP activated kinase AMPK. AMPK activation promotes an increase in NAD+ levels leading to the activation of the SIRT1 deacetylase, which in turn deacetylates and activates PGC-1α. PGC-1α enhances the expression of genes involved in mitochondrial metabolism, thus improving mitochondrial function. On the other hand, calorie rich diets or situations when energy is oversupplied promote the expression of NCoA3, which positively regulates the protein levels of the acetyltransferase KATA2A, which acetylates and decrease the transcriptional activity of PGC-1α. In this metabolic network, the enzyme ATP citrate lyase (ACL) provides the acetyl-CoA required for the enzymatic reaction of acetylation. Finally, stimulation of the cAMP/PKA signaling, as seen after epinephrine and glucagon release, enhances the expression of Sirt1 and the phosphorylation of SIRT1, reinforcing its deacetylase activity to ultimately promote PGC-1α deacetylation.

Figure 4. Molecular model of kinase-mediated control of CRTC2 and HDAC4/5/7 subcellular localization and activity

The metabolic hormones glucagon and insulin signal through the glucagon receptor (GR) and insulin receptor (IR), respectively, to initiate signaling cascades downstream of changes in metabolic status. PKA and LKB1 phosphorylate (orange circles with a P) the AMPKRs (AMPK-Related Kinases), including AMPK and SIK1/2/3 which, when active, phosphorylate CRTC2 and HDAC4/5/7, resulting in their cytoplasmic sequestration. When unphosphorylated, CRTC2 and HDAC4/5/7 translocate to the nucleus (dashed lines) where they are free to promote the activation of gluconeogenic gene expression programs through CREB and the NCoR, HDAC3, FOXO complex, respectively. CRTC2 coactivates CREB, and nuclear FOXO is activated upon HDAC4/5/7-mediated deacetylation (light pink circles). In parallel, AKT phosphorylation regulates the activity of FOXO.