PDF(Pubmed)
Abstract：
In response to insulin stimulation, fat and muscle cells mobilize GLUT4 glucose transporters to the cell surface to enhance glucose uptake. Ubiquitin-like processing of TUG (Aspscr1, UBXD9) proteins is a central mechanism to regulate this process. Here, recent advances in this area are reviewed. The data support a model in which intact TUG traps insulin-responsive \"GLUT4 storage vesicles\" at the Golgi matrix by binding vesicle cargoes with its N-terminus and matrix proteins with its C-terminus. Insulin stimulation liberates these vesicles by triggering endoproteolytic cleavage of TUG, mediated by the Usp25m protease. Cleavage occurs in fat and muscle cells, but not in fibroblasts or other cell types. Proteolytic processing of intact TUG generates TUGUL, a ubiquitin-like protein modifier, as the N-terminal cleavage product. In adipocytes, TUGUL modifies a single protein, the KIF5B kinesin motor, which carries GLUT4 and other vesicle cargoes to the cell surface. In muscle, this or another motor may be modified. After cleavage of intact TUG, the TUG C-terminal product is extracted from the Golgi matrix by the p97 (VCP) ATPase. In both muscle and fat, this cleavage product enters the nucleus, binds PPARγ and PGC-1α, and regulates gene expression to promote fatty acid oxidation and thermogenesis. The stability of the TUG C-terminal product is regulated by an Ate1 arginyltransferase-dependent N-degron pathway, which may create a feedback mechanism to control oxidative metabolism. Although it is now clear that TUG processing coordinates glucose uptake with other aspects of physiology and metabolism, many questions remain about how this pathway is regulated and how it is altered in metabolic disease in humans.
摘要：
为了响应胰岛素刺激，脂肪和肌肉细胞将GLUT4葡萄糖转运蛋白动员到细胞表面以增强葡萄糖摄取。TUG（Aspscr1，UBXD9）蛋白的泛素样加工是调节该过程的核心机制。这里,回顾了该领域的最新进展。数据支持一个模型，在该模型中，完整的TUG通过将囊泡载体与其N末端结合并将基质蛋白与其C末端结合，将胰岛素反应性“GLUT4储存囊泡”捕获在高尔基基质上。胰岛素刺激通过触发TUG的内切蛋白水解裂解释放这些囊泡，由Usp25m蛋白酶介导。裂解发生在脂肪和肌肉细胞中，但不是成纤维细胞或其他细胞类型。完整TUG的蛋白水解加工产生TUGUL，泛素样蛋白质修饰剂，作为N-末端裂解产物。在脂肪细胞中，TUGUL修饰单个蛋白质，KIF5B驱动电机，它将GLUT4和其他囊泡物质带到细胞表面。在肌肉中，这个或另一个电机可以修改。完整的TUG分裂后，通过p97(VCP)ATP酶从高尔基体中提取TUGC-末端产物。在肌肉和脂肪中，这种分裂产物进入细胞核，结合PPARγ和PGC-1α，并调节基因表达以促进脂肪酸氧化和产热。TUGC末端产物的稳定性受Ate1精氨酸基转移酶依赖性N-degron途径的调节，这可能会产生一种反馈机制来控制氧化代谢。虽然现在很清楚，TUG处理协调葡萄糖摄取与生理和代谢的其他方面，关于这条通路是如何调节的，以及它在人类代谢性疾病中是如何改变的，仍然存在许多问题。
