A Selective Autophagy Pathway that Degrades Proteins in Lysosomes

Type II Diabetics is often accompanied by an increased glucose production as a result of enhanced gluconeogenesis in the liver. Molecules that inhibit gluconeogenic enzymes have been shown to reduce glucose production in obesity and diabetic animals. Therefore, understanding how gluconeogenic enzymes are regulated at the molecular level is critical for the development of interventions to better treat Type II Diabetics and obesity. Interestingly, the key gluconeogenic enzyme fructose-1,6-bisphosphatase (FBPase) is found in multiple cellular locations, most notably the plasma membrane, cytosol and nucleus. In primary liver cultures, FBPase is in the cytosol during glucose starvation, but it is imported to the nucleus when glucose starved cells are treated with insulin. In budding yeast, the addition of glucose to starved cells leads to the degradation of FBPase as well as other gluconeogenic enzymes including malate dehydrogenase, isocitrate lyase and phosphoenolpyruvate carboxykinase. These enzymes are degraded in the vacuole via a selective autophagy pathway called the Vid (vacuole import and degradation) pathway. Gluconeogenic enzymes are first targeted to a novel type of vesicles, and these Vid vesicles then merge with endosomes prior to being delivered to the vacuole.

The TOR1 complex plays an important role in cargo recognition and in the formation of Vid vesicles. As with FBPase, TORC1 is found in multiple cellular locations, cycling between the plasma membrane and the vacuole. For example, this complex can be found in endosomes coming from the plasma membrane as well as in retrograde transport vesicles forming from the vacuole membrane. These retrograde transport vesicles contain COPI coatomer proteins, which may play a part in the formation or function of these vesicles. When the Vid pathway is blocked, cargo proteins are targeted to the nucleus. Nuclear distribution can also be seen under conditions of chronological aging, oxidative stress, or rapamycin treatment. Currently, we are studying how the anterograde and retrograde trafficking pathways are co-coordinately regulated. We are also investigating whether the same Vid targeting pathway exists in mammalian cells and whether perturbation of this pathway is linked to Type II Diabetics or other metabolic diseases in human patients.