Summon SUMO to Wrestle with Inflammation

ArticleinMolecular cell 35(6):731-2 · September 2009with1 Reads
DOI: 10.1016/j.molcel.2009.09.002 · Source: PubMed
Abstract
Uncontrolled inflammation contributes to the pathogenesis of inflammatory diseases like atherosclerosis and arthritis, as well as the development of human cancers. Several members of the nuclear receptor (NR) superfamily, including the glucocorticoid receptor (GR), the peroxisome proliferator-activated receptors (PPARs), and the oxysterol (liver X) receptors (LXRs), have the ability to inhibit inflammatory responses (Castrillo and Tontonoz, 2004 and Ogawa et al., 2005). Understanding the molecular basis of NR-mediated anti-inflammatory activity is critical for the development of novel therapeutic drugs against inflammatory disorders.
    • "step of this pathway involves ligand-induced SUMO1 conjugation to K365 within the PPARc ligand-binding domain [22]. Accordingly, ligand-induced SUMOylation of PPARc at lysine 365 specifically by the SUMO1 isoform is repeatedly portrayed in many reviews [1,11,12,23,34,35,36,37,38,39]. Our results do not support the assignment of K365 as a SUMOylation target site as we did not detect any residual SUMOylation of the PPARc K33/ 64/68/77R mutant protein neither in the absence nor in the presence of ligands. "
    [Show abstract] [Hide abstract] ABSTRACT: Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated nuclear receptor regulating adipogenesis, glucose homeostasis and inflammatory responses. The activity of PPARγ is controlled by post-translational modifications including SUMOylation and phosphorylation that affects its biological and molecular functions. Several important aspects of PPARγ SUMOylation including SUMO isoform-specificity and the impact of ligand binding on SUMOylation remain unresolved or contradictory. Here, we present a comprehensive study of PPARγ1 SUMOylation. We show that PPARγ1 can be modified by SUMO1 and SUMO2. Mutational analyses revealed that SUMOylation occurs exclusively within the N-terminal activation function 1 (AF1) domain predominantly at lysines 33 and 77. Ligand binding to the C-terminal ligand-binding domain (LBD) of PPARγ1 reduces SUMOylation of lysine 33 but not of lysine 77. SUMOylation of lysine 33 and lysine 77 represses basal and ligand-induced activation by PPARγ1. We further show that lysine 365 within the LBD is not a target for SUMOylation as suggested in a previous report, but it is essential for full LBD activity. Our results suggest that PPARγ ligands negatively affect SUMOylation by interdomain communication between the C-terminal LBD and the N-terminal AF1 domain. The ability of the LBD to regulate the AF1 domain may have important implications for the evaluation and mechanism of action of therapeutic ligands that bind PPARγ.
    Full-text · Article · Jun 2013
    • "These findings suggest that typical activators of these pathways might have an impact on the SUMOylation of these putative or proven substrates of SUMO conjugation. SUMOylation can indeed be regulated through multiple mechanisms8990919293. It has been shown that the expression of various components of the SUMOylation system is regulated under certain physiological or pathogenic conditions. "
    [Show abstract] [Hide abstract] ABSTRACT: SUMOylation contributes to the regulation of many essential cellular factors. Diverse techniques have been used to explore the functional consequences of protein SUMOylation. Most approaches consider the identification of sequences on substrates, adaptors, or receptors regulating the SUMO conjugation, recognition, or deconjugation. The large majority of the studied SUMOylated proteins contain the sequence [IVL]KxE. SUMOylated proteins are recognized by at least 3 types of hydrophobic SUMO-interacting motifs (SIMs) that contribute to coordinate SUMO-dependent functions. Typically, SIMs are constituted by a hydrophobic core flanked by one or two clusters of negatively charged amino acid residues. Multiple SIMs can integrate SUMO binding domains (SBDs), optimizing binding, and control over SUMO-dependent processes. Here, we present a survey of the methodologies used to study SUMO-regulated functions and provide guidelines for the identification of cis and trans sequences controlling SUMOylation. Furthermore, an integrative analysis of known and putative SUMO substrates illustrates an updated landscape of several SUMO-regulated events. The strategies and analysis presented here should contribute to the understanding of SUMO-controlled functions and provide rational approach to identify biomarkers or choose possible targets for intervention in processes where SUMOylation plays a critical role.
    Full-text · Article · Jul 2012
    • "These findings suggest that typical activators of these pathways might have an impact on the SUMOylation of these putative or proven substrates of SUMO conjugation. SUMOylation can indeed be regulated through multiple mechanisms8990919293. It has been shown that the expression of various components of the SUMOylation system is regulated under certain physiological or pathogenic conditions. "
    [Show abstract] [Hide abstract] ABSTRACT: Received 9 March 2012; Accepted 12 April 2012Academic Editor: Philip Coffino
    Full-text · Article · Jan 2012 · PLoS ONE
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