Pore-forming protein βγ-CAT drives extracellular nutrient scavenging under cell starvation

Abstract

Nutrient acquisition is essential for cells. {beta}{gamma}-CAT is a pore-forming protein (PFP) and trefoil factor complex assembled under tight regulation identified in toad Bombina maxima. Here, we reported that B. maxima cells secreted {beta}{gamma}-CAT under glucose and glutamine deficiency to scavenge extracellular proteins for their nutrient supply and survival. AMP-activated kinase signaling positively regulated the expression and secretion of {beta}{gamma}-CAT. The PFP complex promoted albumin and ovalbumin uptake through endolysosomal pathways. Elevated intracellular amino acids, enhanced ATP production, and eventually prolonged cell survival were observed in the presence of {beta}{gamma}-CAT and extracellular albumin or ovalbumin. Liposome assays indicated that high concentration of ATP (around 1-5 mM) negatively regulated the opening of {beta}{gamma}-CAT channels. Collectively, these results uncovered that {beta}{gamma}-CAT is an essential element in cell nutrient scavenging under cell starvation by driving vesicular uptake of extracellular proteins, providing a new paradigm for PFPs in cell nutrient acquisition and metabolic flexibility.