Posttranslational Modifications of Lipid-Activated Nuclear Receptors: Focus on Metabolism

Abstract

Posttranslational modifications (PTMs) occur to nearly all proteins, are catalyzed by specific enzymes, and are subjected to tight regulation. They have been shown to be a powerful means by which the function of proteins can be modified, resulting in diverse effects. Technological advances such as the increased sensitivity of mass spectrometry-based techniques and availability of mutant animal models have enhanced our understanding of the complexities of their regulation and the effect they have on protein function. However, the role that PTMs have in a pathological context still remains unknown for the most part. PTMs enable the modulation of nuclear receptor function in a rapid and reversible manner in response to varied stimuli, thereby dramatically altering their activity in some cases. This review focuses on acetylation, phosphorylation, SUMOylation, and O-GlcNAcylation, which are the 4 most studied PTMs affecting lipid-regulated nuclear receptor biology, as well as on the implications of such modifications on metabolic pathways under homeostatic and pathological situations. Moreover, we review recent studies on the modulation of PTMs as therapeutic targets for metabolic diseases.

Figure 1.

Posttranslational modifications on lipid-activated NRs. Residues modified by acetylation (dark gray), phosphorylation (light gray), and SUMOylation (black) are shown.

Figure 2.

Changes in posttranslational modifications and their effects on FXR activity under physiological (A) or pathological (B) conditions. In homeostatic conditions (A), there is a tight regulation between p300-mediated acetylation and Sirt1-mediated deacetylation of FXR. In parallel, other modifications such as phosphorylation and SUMOylation have also been proven to regulate FXR actions. However, a pathological increase in FXR acetylation (B) and subsequent dysregulated FXR activity leads to increased inflammatory gene expression and decreased target gene expression.

Figure 3.

Effects of posttranslational modifications on LXR transcriptional activation (A) and transrepression (B). (A) Deacetylation by LXR agonists or O-GlcNAcylation by glucose induces LXR target gene expression, whereas phosphorylation has a gene-specific effect. (B) LXR transrepression of inflammatory gene expression is promoted by SUMOylation of the receptor, which consequently increases LXR avidity for the NCoR complex.