GAPDH inhibits intracellular pathways during starvation for cellular energy homeostasis

Starvation poses a fundamental challenge to cell survival. How autophagy promotes energy homeostasis in this setting has been extensively characterized (1), but how other mechanisms may be similarly critical is less understood. Here, we initially find that glyceraldehyde 3-phosphate dehydrogenase (GAPDH) inhibits Coat Protein I (COPI) transport by targeting a GTPase-activating protein (GAP) against ADP-Ribosylation Factor 1 (ARF1) to suppress COPI vesicle fission. We then find that GAPDH inhibits multiple other transport pathways also by targeting ARF GAPs. Defining a physiologic role for this broad inhibition, our results suggest that it is activated by the cell during starvation to reduce energy consumption in promoting energy homeostasis. These findings reveal a previously unappreciated level of coordination among the intracellular transport pathways, with this process underlying a new critical mechanism of cellular energy homeostasis.