Autophagy proteins in macroendocytic engulfment

Abstract

Eukaryotic cells must constantly degrade both intracellular and extracellular material to maintain cellular and organismal homeostasis. Two engulfment pathways, autophagy and phagocytosis, contribute to the turnover of intracellular and extracellular substrates by delivering material to the lysosome. Historically these are thought to be separate pathways, but recent studies have revealed the direct participation of autophagy proteins in phagocytosis. Autophagy proteins lipidate LC3 onto phagosomes and other macroendocytic vacuole membranes, and are required for lysosomal degradation of engulfed cargo, demonstrating an autophagosome-independent role for autophagy proteins in mediating the turnover of extracellular substrates. This review discusses the biological systems in which autophagy proteins have been found to regulate lysosome fusion to non-autophagic membranes.

Figure 1

Autophagy proteins involved in autophagy and macroendocytic degradation pathways. (A) Autophagy pathway. In the presence of growth factors and amino acids, mTor associates with and inactivates the Ulk complex by phosphorylating Atg13 and Ulk1. Upon starvation and release of mTor inhibition, the active complex localizes to a membrane source and acts in concert with the Vps34-ATG14L complex to recruit and activate components of the LC3 and Atg12 ubiquitin-like conjugation systems. LC3 is lipidated onto forming double-membrane autophagosomes. After lysosome fusion, LC3 is de-lipidated and recycled by Atg4. (B) Macroendocytic engulfment. Following phagocytosis or related macroendocytic engulfment mechanisms, signals dependent on activation of TLRs, FcγR, or other uncharacterized receptors, which are not fully understood but include ROS, are transmitted across the vacuole to recruit and activate a Vps34 complex and the LC3 and Atg12 conjugation systems. LC3 is lipidated directly to the single-membrane vacuole, followed by lysosome fusion. Both degradation pathways in (A) and (B) utilize common Vps34 and LC3 and Atg12 conjugation machinery, but differ in upstream activation mechanisms.