Prof William Hlavacek (Theoretical Division, Los Alamos National Laboratory, USA & Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Germany) visited our group and gave a talk on "A molecular switch: mutual inhibition of MTORC1 and ULK1".
Abstract: 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.
Reference: Szymańska P, Martin KR, MacKeigan JP, Hlavacek WS, Lipniacki T (2015) Computational analysis of an autophagy/translation switch based on mutual inhibition of MTORC1 and ULK1. PLOS ONE 10: e0116550.