Functional Role of Autophagy-Mediated Proteome Remodeling in Cell Survival Signaling and Innate Immunity

• Published in: Molecular cell Vol. 55; no. 6; pp. 916 - 930
• Main Authors: Mathew, Robin, Khor, Sinan, Hackett, Sean R., Rabinowitz, Joshua D., Perlman, David H., White, Eileen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.09.2014; Elsevier
• Subjects: Animals; Autophagy; carcinogenesis; Cell Line, Tumor; Cell Survival; cell viability; free amino acids; Humans; Immunity, Innate; inflammation; metabolism; Mice; neoplasm cells; neoplasms; organelles; physiological transport; Protein Transport; proteins; proteome; Proteome - physiology; ras Proteins - genetics; starvation; Transport Vesicles
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2014.07.019

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. [Display omitted] •Autophagy selectively remodels the majority of the cellular proteome in starvation•Proteins that facilitate autophagy are preserved by starvation-induced autophagy•Autophagy prevents accumulation of proinflammatory signaling pathway components•Autophagy defects prime cells for the interferon response While autophagy is known to degrade proteins, it is unclear whether it selectively alters cellular function. Mathew et al. show that autophagy selectively alters the global cellular proteome. Proteome remodeling by autophagy deficiency causes accumulation of proinflammatory proteins, priming cells for subsequent activation of the interferon response and cell death.