Uncovering the biological role of nuclear receptor peroxisome proliferator-activated receptors (PPARs) has greatly advanced our knowledge of the transcriptional control of glucose and energy metabolism. As such, pharmacological activation of PPARγ has emerged as an efficient approach for treating metabolic disorders with the current use of thiazolidinediones to improve insulin resistance in diabetic patients. The recent identification of growth hormone releasing peptides (GHRP) as potent inducers of PPARγ through activation of the scavenger receptor CD36 has defined a novel alternative to regulate essential aspects of lipid and energy metabolism. Recent advances on the emerging role of CD36 and GHRP hexarelin in regulating PPARγ downstream actions with benefits on atherosclerosis, hepatic cholesterol biosynthesis and fat mitochondrial biogenesis are summarized here. The response of PPARγ coactivator PGC-1 is also discussed in these effects. The identification of the GHRP-CD36-PPARγ pathway in controlling various tissue metabolic functions provides an interesting option for metabolic disorders.

Anophthalmia and/or microphthalmia, pulmonary hypoplasia, diaphragmatic hernia, and cardiac defects are the main features of PDAC syndrome. Recessive mutations in STRA6, encoding a membrane receptor for the retinol-binding protein, have been identified in some cases with PDAC syndrome, although many cases have remained unexplained. Using whole-exome sequencing, we found that two PDAC-syndrome-affected siblings, but not their unaffected sibling, were compound heterozygous for nonsense (c.355C>T [p.Arg119(∗)]) and frameshift (c.1201_1202insCT [p.Ile403Serfs(∗)15]) mutations in retinoic acid receptor beta (RARB). Transfection studies showed that p.Arg119(∗) and p.Ile403Serfs(∗)15 altered RARB had no transcriptional activity in response to ligands, confirming that the mutations induced a loss of function. We then sequenced RARB in 15 subjects with anophthalmia and/or microphthalmia and at least one other feature of PDAC syndrome. Surprisingly, three unrelated subjects with microphthalmia and diaphragmatic hernia showed de novo missense mutations affecting the same codon; two of the subjects had the c.1159C>T (Arg387Cys) mutation, whereas the other one carried the c.1159C>A (p.Arg387Ser) mutation. We found that compared to the wild-type receptor, p.Arg387Ser and p.Arg387Cys altered RARB induced a 2- to 3-fold increase in transcriptional activity in response to retinoic acid ligands, suggesting a gain-of-function mechanism. Our study thus suggests that both recessive and dominant mutations in RARB cause anophthalmia and/or microphthalmia and diaphragmatic hernia, providing further evidence of the crucial role of the retinoic acid pathway during eye development and organogenesis.

c SUMO conjugation has emerged as a dynamic process in regulating protein function. Here we identify estrogen receptor ␤ (ER␤) to be a new target of SUMO-1. ER␤ SUMO-1 modification occurs on a unique nonconsensus sumoylation motif which becomes fully competent upon phosphorylation of its contained serine residue, which provides the essential negative charge for sumoylation. This process is further regulated by phosphorylation of additional adjacent serine residues by glycogen synthase kinase 3␤ (GSK3␤), which maximizes ER␤ sumoylation in response to hormone. SUMO-1 attachment prevents ER␤ degradation by competing with ubiquitin at the same acceptor site and dictates ER␤ transcriptional inhibition by altering estrogen-responsive target promoter occupancy and gene expression in breast cancer cells. These findings uncovered a novel phosphorylated sumoylation motif (pSuM), which consists of the sequence KXS (where represents a large hydrophobic residue) and which is connected to a GSK3-activated extension that functions as a SUMO enhancer. This extended pSuM offers a valuable signature to predict SUMO substrates under protein kinase regulation. Sumoylation is a highly dynamic posttranslational process that consists of conjugation of the small ubiquitin-like modifier SUMO on target proteins (20). SUMO modification is involved in diverse aspects of protein function which are often linked to nuclear activities, such as DNA replication, genome stability, nuclear transport, and gene transcription (41). Despite a low and transient stoichiometric proportion of SUMO-modified proteins, an increasing number of substrates have been characterized mostly on the basis of the presence of a predicted minimal core SUMO consensus motif, KXE/D (where represents a large hydrophobic residue), in which the lysine serves as the acceptor site to covalently link SUMO (35). The sequential enzymatic events leading to protein sumoylation closely resemble those of ubiquitination (13). The core SUMO motif is recognized by the unique 17␤-estradiol (E2)-conjugating enzyme Ubc9, which upon transfer from E1-activating enzyme 1 (SAE1)/SAE2 conjugates SUMO onto a specific lysine residue. Although Ubc9 is sufficient to promote sumoylation, three classes of E3 ligases that consist of the nucleoporin RanBP2, the polycomb repressor Pc2, and the PIAS ligase family members have been described to facilitate the conjugation process. Sumoylation is reversible, as the SUMO tags can rapidly be cleaved from target proteins by the SENP family of sentrin-specific isopeptidases, which ensure the dynamic and appropriate maintenance of SUMO substrates (24). Recently, two different extensions following the KXE/D motif have been found to enhance substrate sumoylation for some targets: the phosphorylation-dependent sumoylation motif (PDSM), which consists of the sequence KXEXXpSP (21), and the negatively charged amino acid-dependent sumoylation motif (NDSM), which is characterized by a cluster of acidic residues (51). As both motifs share a feature of negatively charged ...

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Retinoic acid (RA) signaling plays a key role in the development and function of several systems in mammals. We previously discovered that the de novo mutations c.1159C>T (p.Arg387Cys) and c.1159C>A (p.Arg387Ser) in the RA Receptor Beta (RARB) gene cause microphthalmia and diaphragmatic hernia. However, the natural history of affected subjects beyond the prenatal or neonatal period was unknown. Here, we describe nine additional subjects with microphthalmia who have de novo mutations in RARB, including the previously described p.Arg387Cys as well as the novel c.887G>C (p.Gly296Ala) and c.638T>C (p.Leu213Pro). Moreover, we review the information on four previously reported cases. All subjects who survived the neonatal period (n = 10) displayed severe global developmental delay with progressive motor impairment due to spasticity and/or dystonia (with or without chorea). The majority of subjects also showed Chiari type I malformation and severe feeding difficulties. We previously found that p.Arg387Cys and p.Arg387Ser induce a gain-of-function. We show here that the p.Gly296Ala and p.Leu213Pro RARB mutations further promote the RA ligand-induced transcriptional activity by twofold to threefold over the wild-type receptor, also indicating a gain-of-function mechanism. These observations suggest that precise regulation of RA signaling is required for brain development and/or function in humans.