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Review
. 2012 Feb 1;302(3):H515-26.
doi: 10.1152/ajpheart.00703.2011. Epub 2011 Oct 28.

The story so far: post-translational regulation of peroxisome proliferator-activated receptors by ubiquitination and SUMOylation

Kristine M Wadosky  1 , Monte S Willis
Affiliations
Review

The story so far: post-translational regulation of peroxisome proliferator-activated receptors by ubiquitination and SUMOylation

Kristine M Wadosky et al. Am J Physiol Heart Circ Physiol. .

Erratum in

  • Am J Physiol Heart Circ Physiol. 2014 Aug 1;307(3):H464-6

Abstract

Many studies have implicated the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptor transcription factors in regulating cardiac substrate metabolism and ATP generation. Recently, evidence from a variety of cell culture and organ systems has implicated ubiquitin and small ubiquitin-like modifier (SUMO) conjugation as post-translational modifications that regulate the activity of PPAR transcription factors and their coreceptors/coactivators. Here we introduce the ubiquitin and SUMO conjugation systems and extensively review how they have been shown to regulate all three PPAR isoforms (PPARα, PPARβ/δ, and PPARγ) in addition to the retinoid X receptor and PPARγ coactivator-1α subunits of the larger PPAR transcription factor complex. We then present how the specific ubiquitin (E3) ligases have been implicated and review emerging evidence that post-translational modifications of PPARs with ubiquitin and/or SUMO may play a role in cardiac disease. Because PPAR activity is perturbed in a variety of forms of heart disease and specific proteins regulate this process (E3 ligases), this may be a fruitful area of investigation with respect to finding new therapeutic targets.

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Figures

Fig. 1.
Fig. 1.
Ubiquitination and small uniquitin-like modifier (SUMO)ylation of the peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor (RXR)/PPARγ coactivator 1α (PGC-1α) complex. Ubiquitination (A) and SUMOylation (B) are multistep processes using E1, E2, and E3 enzymes to posttranslationally modify substrates (described in text). C: canonical ubiquitination (top) occurs by ubiquitin chains placed by the E2/E3 complex whereby the interubiquitin links occur through their lysine-48 (K48). Substrates modified with ubiquitin chains linked by their K48 are generally targeted for degradation by the 26S proteasome. Both atypical ubiquitination (linkages between ubiquitin such as K63, middle) and monoubiquitination (bottom) generally target substrates to change localization which can affect activity (discussed in text). D: PPAR/RXR/PGC-1 complex may be ubiquitinated and/or SUMOylated on each of their subunits, allowing for complex and nuanced regulation of PPAR activity. Here we represent a composite theoretical view of the post-translational modifications that may occur on RXRα, PPAR isoforms, and PGC-1 complex during PPAR signaling, indicating the potential complexity by which cardiac PPARs may be regulated. Vertebrates have 4 SUMO isoforms, 3 of which have been found to be involved in post-translational modification of proteins (SUMO-4 is predicted to be a pseudogene). *SUMO-1, SUMO-2, or SUMO-3. SUMO-2 and SUMO-3 (**) have the presence of a motif that allows for the polySUMOylation of substrates, whereas SUMO-1 ($) is mainly involved in monoSUMOylation. U, ubiquitination; S, SUMO; AOS1, activator of SUMO1; UBA2, ubiquitin-like modifier activating enzyme 2; UBC9, ubiquitin-conjugating enzyme 9; PPRE, PPAR response element.
Fig. 2.
Fig. 2.
Summary of reported SUMOylation sites and regions necessary for ubiquitination on PPAR nuclear receptors. Like all nuclear receptors, PPARα, PPARβ/δ, and PPARγ are modular in structure and contain 5 domains, indicated by A, B, C, D, E, and F. The A/B region contains the activation function-1 region (AF-1) where the activity in the presence of ligand is found (95). AF-1 activation is normally weak but synergizes with the activation function-2 region (AF-2) found in the E domain upon ligand binding, resulting in an increase in transcription activity and gene expression. The DNA binding domain (DBD) is found in the C domain and binds specific DNA sequences in the PPREs found in the promoter regions of genes regulated by PPARs. The D domain contains the hinge region, connecting the DBD to the ligand binding domain (LBD) found in domain E. The LBD contributes to the dimerization of the receptor with RXR and binds coactivator and corepressor proteins here. The E domain also contains the AF-2 domain, whose action is dependent on ligand binding (95). Both domains E and F have been implicated in the dimerization of PPARs with RXR and ligand-dependent transactivation (47, 63). Recent studies have described the specific sites within PPARα, PPARβ/δ, and PPARγ at which SUMOylation occurs (above each PPAR isoform) or, more broadly, that ubiquitination occurs (below each PPAR isoform). The specific amino acids where SUMO modifications have been reported are indicated by the lysine (K) position in the PPAR amino acid sequence. Lysines in the 185, 358, 185, 77/107, and 365/395 positions have been reported as indicated above. For more experimental detail leading to these findings, see Table 1. N, NH2 terminus; C, COOH terminus.
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