Colloquium Natural and Life Sciences - - William Hlavacek (Systems Biology)

Protein synthesis, which uses nutrients, and autophagy, which generates nutrients through recycling of cytoplasmic constituents, are coordinately regulated by an intricate regulatory system, in which three serine/threonine-specific protein kinases, AMPK, MTOR and ULK1, are central. Recently, it has been discovered that MTOR and ULK1 repress one another. Here, through construction and analysis of a computational model, we show that mutual inhibition of MTOR and ULK1 may allow activation of autophagy and protein synthesis in a mutually exclusive, all-or-none manner. Moreover, when mutual inhibition is combined with slow negative feedback from ULK1 to AMPK, these regulatory processes may generate oscillatory behavior: alternating periods of autophagy and protein synthesis, during which building blocks for protein synthesis are first generated (through autophagic recycling) and then used. These predicted behaviors may be important for the orderly coordination of autophagy and protein synthesis and proper responses to changes in cellular energy and nutrient levels. If validated experimentally, these insights into the system-level consequences of molecular mechanisms regulating autophagy could be useful for finding ways to therapeutically manipulate autophagy, which plays a role in aging, immunity, and diverse diseases, including cancer and neurodegeneration.