The N-degron pathway regulates glucose and insulin homeostasis through the lysosomal degradation of RXRA/RXRα via SQSTM1/p62.

Central to the pathogenesis of type 2 diabetes (T2D) is the failure in insulin secretion from pancreatic β-cells associated with insulin resistance. The nuclear receptor RXRA/RXRα (retinoid X receptor alpha) is a transcriptional regulator of insulin secretion and systemic glucose metabolism. Here, we show that the macroautophagic/autophagic receptor SQSTM1/p62 (sequestosome 1) sequesters RXRA for lysosomal degradation to modulate glucose metabolism and insulin secretion. Under glucolipotoxicity, RXRA is released from SQSTM1 to inhibit mitochondrial respiration and insulin secretion and to induce lipogenesis. SQSTM1-dependent degradation of RXRA was reconstituted in vitro and mice using ATB1002, a chemical N-degron designed to bind and activate SQSTM1 as an N-recognin of the N-degron pathway. In prediabetic and T2D models, SQSTM1 agonists induced the lysosomal degradation of RXRA, and enhanced glucose-stimulated insulin secretion and insulin responsiveness. These results identify SQSTM1 as a master regulator in glucose metabolism and insulin secretion, providing a therapeutic means to treat T2D.Abbreviations: ATLs: autophagy targeting ligands; AUC: area under the curve; ATP: adenosine triphosphate; co-IP: co-immunoprecipitation; GSIS: glucose-stimulated insulin secretion; GTT: glucose tolerance test; HFD: high-fat diet; i.p.: intraperitoneally; LBD: ligand binding domain; NR1H3/LXRα: nuclear receptor subfamily 1 group H member 3; Nt: N-terminal; PPARG/PPARγ: peroxisome proliferator activated receptor gamma; RER: respiratory exchange ratio; RXRA/RXRα: retinoid X receptor alpha; SQSTM1/p62: sequestosome 1; T2D: type 2 diabetes; TG: triglycerides; TIW: three times per week; UBA: ubiquitin-associated domain; ZZ: zinc finger.