The Roles of SUMO in Metabolic Regulation

Abstract

Protein modification with the small ubiquitin-related modifier (SUMO) can affect protein function, enzyme activity, protein-protein interactions, protein stability, protein targeting and cellular localization. SUMO influences the function and regulation of metabolic enzymes within pathways, and in some cases targets entire metabolic pathways by affecting the activity of transcription factors or by facilitating the translocation of entire metabolic pathways to subcellular compartments. SUMO modification is also a key component of nutrient- and metabolic-sensing mechanisms that regulate cellular metabolism. In addition to its established roles in maintaining metabolic homeostasis, there is increasing evidence that SUMO is a key factor in facilitating cellular stress responses through the regulation and/or adaptation of the most fundamental metabolic processes, including energy and nucleotide metabolism. This review focuses on the role of SUMO in cellular metabolism and metabolic disease.

Keywords: Lipids; Metabolic disease; Metabolism; One-carbon metabolism; SUMO.

Fig. 9.1

The sumoylation of SREBPs recruits a co-repressor complex which includes HDAC3. The recruitment of HDAC3 containing complex reduces the transcriptional activity of SREBPs. SUMO is only required for the formation of the co-repressor complex, as the complex continues to repress once SUMO is removed. Alternatively, SREBPs can be phosphorylated by MAPKs which inhibit sumoylation by competing for sites nearby the sumoylation motif. SREBP phosphorylation allows for transcriptional activation of lipid biosynthesis by expressing genes that contain sterol-response elements

Fig. 9.2

(a) Under basal conditions, SUMO modified KLF5 is part of a co-repressor complex that contains unliganded PPAR-δ. The KLF5 co-repressor complex inhibits the transcription of the lipid oxidation gene Cpt1b and uncoupling protein genes Ucp2 and Ucp3. (b) Upon PPAR-δ ligand stimulation, KLF5 is desumoylated by SENP1 allowing for the exchange of co-repressors for co-activators. (c) Desumoylation of KLF induces the interaction of KLF5 and PPAR-δ allowing for the induction of Cpt1b, Ucp2, and Ucp3 transcription

Fig. 9.3

Compartmentation of folate-mediated one-carbon metabolism in the cytoplasm, mitochondria, and nucleus. One-carbon metabolism in the cytoplasm is required for the de novo synthesis of purines and thymidylate, and for remethylation of homocysteine to methionine. One-carbon metabolism in the nucleus synthesizes dTMP from dUMP and serine. AICARTfase, aminoimidazole-4-carboxamide ribonucleotide transferase; DHFR, dihydrofolate reductase; GARTfase, 10-formyltetrahydrofolate:5′-phosphoribosylglycinamide N-formyltransferase; MTHFD1, Methylenetetrahydrofolate Dehydrogenase; NADPH, nicotinamide adenine dinucleotide phosphate; SHMT1, Cytoplasmic Serine Hydroxymethyltrasferase; TYMS, Thymidylate Synthase; THF, tetrahydrofolate