SignificanceThe final step of cell division, abscission, is temporally regulated by the Aurora B kinase and charged multivesicular body protein 4C (CHMP4C) in a conserved pathway called the “abscission checkpoint” which arrests abscission in the presence of lingering mitotic problems. Despite extensive study, the physiological importance of this pathway to human health has remained elusive. We now demonstrate that a cancer-predisposing polymorphism in CHMP4C disrupts the abscission checkpoint and results in DNA damage accumulation. Moreover, deficits in this checkpoint synergize with p53 loss and generate aneuploidy under stress conditions that increase the frequency of chromosome missegregation. Therefore, cells expressing the cancer-associated polymorphism in CHMP4C are genetically unstable, thus suggesting an oncogenic mechanism that may involve the dysregulation of abscission.
Insulin stimulates glucose transport by delivering GLUT4 from a specialized storage compartment to the plasma membrane. Subcellular fractionation and an in vitro assay for GLUT4-storage vesicle formation show that the Sec1/Munc18 protein mVps45 is required to correctly sort GLUT4 into this compartment.
The levels of expression, distribution, and association of all of the VAMPs expressed in 3T3-L1 adipocytes are characterized. This is the first systematic analysis of all members of this protein family for any cell type.
Key to whole body glucose homeostasis is the ability of fat and muscle cells to sequester the facilitative glucose transporter GLUT4 in an intracellular compartment from where it can be mobilized in response to insulin. We have previously demonstrated that this process requires ubiquitination of GLUT4 while numerous other studies have identified several molecules that are also required, including the insulin-responsive aminopeptidase IRAP and its binding partner, the scaffolding protein tankyrase. In addition to binding IRAP, Tankyrase has also been shown to bind the deubiquinating enzyme USP25. Here we demonstrate that USP25 and Tankyrase interact, and colocalise with GLUT4 in insulin-sensitive cells. Furthermore depletion of USP25 from adipocytes reduces cellular levels of GLUT4 and concomitantly blunts the ability of insulin to stimulate glucose transport. Collectively, these data support our model that sorting of GLUT4 into its insulin-sensitive store involves a cycle of ubiquitination and subsequent deubiquitination.
The facilitative glucose transporter type 4 (GLUT4) is expressed in adipose and muscle and plays a vital role in whole body glucose homeostasis. In the absence of insulin, only ~1% of cellular GLUT4 is present at the plasma membrane, with the vast majority localizing to intracellular organelles. GLUT4 is retained intracellularly by continuous trafficking through two inter-related cycles. GLUT4 passes through recycling endosomes, the trans Golgi network and an insulin-sensitive intracellular compartment, termed GLUT4-storage vesicles or GSVs. It is from GSVs that GLUT4 is mobilized to the cell surface in response to insulin, where it increases the rate of glucose uptake into the cell. As with many physiological responses to external stimuli, this regulated trafficking event involves multiple posttranslational modifications. This review outlines the roles of posttranslational modifications of GLUT4 on its function and insulin-regulated trafficking.
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