Amphibian βγ-CAT Defines a Pore-Forming Protein System for Nutrient Acquisition and Metabolic Flexibility

Cell membranes form selective barriers for the exchange of materials between cells and their environment. Nutrient uptake in metazoan cells is generally mediated by membrane transporters and endolysosomal pathways. βγ-CAT, an aerolysin family pore-forming protein (PFP)–trefoil factor complex identified in the toad Bombina maxima, has been characterized as a novel regulator of nutrient acquisition. First, the toad cells dispatch βγ-CAT under starvation to scavenge extracellular proteins for their energy supply and survival. Second, blood βγ-CAT is an immediate responsive element under fasting, which is able to mediate the transcellular transport of albumin-bound fatty acids for the nutrient requirement of tissue parenchymal cells. Third, βγ-CAT mediates macropinocytosis in toad osmoregulatory organs for facilitating toad water maintaining. This PFP complex has been found to be tightly regulated at several stages by toad endogenous elements, like AMP-activated kinase signaling, IgG Fc-binding protein, its PFP paralog and ATP. Insights from βγ-CAT define a previously unrecognized PFP system that drives vesicular delivery and transport. Notably, similar functions and regulatory strategies are now being progressively validated in other species, providing a new paradigm for PFP-driven nutrient acquisition and metabolic flexibility.