Shengcai Lin – Sensing Metabolic Stresses and Reprogramming of Metabolic Pathways

Speaker: Shengcai Lin

Title: Sensing Metabolic Stresses and Reprogramming of Metabolic Pathways

Abstract:

Metabolic homeostasis is maintained by various cellular sensors, including the master kinases AMPK (AMP-activated protein kinase) and mTORC1. In response to low energy status, AMPK is activated to enhance catabolic activities with concurrent inhibition of anabolic processes such as fatty acid synthesis. In contrast, mTORC1 is activated when nutrients and growth factors are abundant. Previously, we discovered the mechanism by which AMP, as a low energy-charge signal, can autonomously initiate the assembly of an activating complex for AMPK in response to starvation. AMP binding causes a higher affinity of AMPK for the scaffold protein AXIN that also binds to LKB1, thereby promoting phosphorylation and activation of AMPK. More recently, we found most surprisingly that the late endosomal/lysosomal protein complex v-ATPase-Ragulator, essential for activation of mTORC1, is also required for AMPK activation. We also uncovered that AMPK is a residential protein of late endosome/lysosome. Under glucose starvation, the v-ATPase-Ragulator complex is accessible to AXIN/LKB1 for AMPK activation. Concurrently, mTORC dissociates from endosome and becomes inactivated. We have thus revealed a switch between catabolism and anabolism. Most recently, we have uncovered other functions of ULK1/2 kinases than initiation of autophagy. We found that ULK1 functions to regulate glycolytic pathways by direct phosphorylation of multiple glycolytic enzymes. The functional outcome of the modulation of the enzymatic activities by ULK1 will be presented at the talk.