Ras-driven
cancer cells upregulate basal autophagy that degrades and recycles intracellular
proteins and organelles. Autophagy-mediated
proteome degradation provides free
amino acids to support metabolism and macromolecular synthesis, which confers a survival advantage in
starvation and promotes
tumorigenesis. While the degradation of isolated
protein substrates by autophagy has been implicated in controlling cellular function, the extent and specificity by which autophagy remodels the cellular
proteome and the underlying functional consequences were unknown. Here we compared the global
proteome of autophagy-functional and -deficient Ras-driven
cancer cells, finding that autophagy affects the majority of the
proteome yet is highly selective. While levels of vesicle trafficking
proteins important for autophagy are preserved during
starvation-induced autophagy, deleterious inflammatory response pathway components are eliminated even under basal conditions, preventing
cytokine-induced paracrine cell death. This reveals the global, functional impact of autophagy-mediated
proteome remodeling on cell survival and identifies critical autophagy substrates that mediate this process.