Editors' ChoiceAtherosclerosis

Sumo Wrestling Atherosclerosis

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Science Translational Medicine  17 Sep 2014:
Vol. 6, Issue 254, pp. 254ec158
DOI: 10.1126/scitranslmed.3010406

Nuclear receptors (NRs) are responsible for sensing hormones and other molecules involved in development, homeostatis, and metabolism. These receptors can then directly bind DNA, regulating the expression of specific genes. NRs play a prominent role in metabolic homeostasis as well pathogenesis of chronic inflammatory and metabolic diseases such as diabetes and atherosclerosis. Liver receptor homolog-1 (LRH1), a member of the NR5A family, is expressed mainly in the intestine and liver and regulates diverse metabolic functions. Among the transcriptional targets of LRH1 are genes that regulate cholesterol metabolism and reverse cholesterol transport, but whether LRH1 is involved in reverse cholesterol transport in vivo and can contribute to atherosclerosis pathogenesis is not known. Moreover, LRH transcriptional activity can be regulated through a posttranslational modification known as SUMOylation, where small ubiquitin-like modifier (SUMO) proteins are covoalently transferred on and off to target proteins to modify their functions. How SUMOylation regulates the activity of LRH1 is not clear. The physiological significance of SUMOylation of LRH1—as for most other NRs—remains a mystery.

A new study by Stein et al. shows that SUMOylation status of a single lysine residue on LRH1 can alter the course of atherosclerosis. Mutation of a specific lysine on the SUMO acceptor motif to an argine (K286R) diminishes SUMOylation of LRH1 and leads to enhanced transcription of some of its hepatic targets, including cholesterol metabolism genes. To understand the functional importance of this posttranslational modification, the researchers generated a knock-in mouse model harboring the K289R SUMOylation-defective mutation on the atherosclerosis prone, low-density lipoprotien receptor–deficient (Ldlr–/–) background. The SUMOylation-defective mutant mice displayed significantly reduced atherosclerosis. Furthermore, the study showed SUMOylation status of LRH1 governs its interaction with the co-repressor prosperso homeobox protein 1 (PROX1). When the association of PROX1 with the SUMOylation-defective LRH1 is lost, a subset of LRH-1 target genes, including those that control cholesterol homeostasis, are activated in the liver. The SUMOylation-defective LRH1 mutant can promote reverse cholesterol transport in vivo and stimulate bile excretion. These findings demonstrate that posttranslational modification of a single amino acid can have a substantial impact on the pathogenesis of a complex disease such as atherosclerosis. The study sparks an interest in defining new pharmacological strategies that alter SUMOylation for selective regulation of NR target genes in a tissue- and disease-specific manner.

S. Stein et al., SUMOylation-dependent LRH-1/PROX1 interaction promotes atherosclerosis by decreasing hepatic reverse cholesterol transport. Cell Metab. 10.1016/j.cmet.2014.07.023 (2014). [Abstract]

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