A systems biology viewpoint on autophagy in health and disease

Autophagy is a homeostatic process, conserved in alleukaryotes, whereby cellular contents can be deliveredto the lysosome to yield recyclable nutrient componentsand rid cells of potentially deleterious proteins, orga-nelles and pathogens. Operating in concert with theubiquitin/proteasomesystem,autophagyplaysavitalroleinhomeostasisandthecellularresponsestostresses,suchas infection, nutrient starvation, endoplasmic reticulumstress, and mitochondrial damage.The process of autophagy proceeds through a sequenceofstages,beginningwithnucleationofautophagicvesiclein response to stress signals, followed by elongation andclosure of autophagosome membrane to engulf targetedcytoplasmic constituents, docking and fusion of theautophagosome with lysosomes to form autolysosomes,andfinallydegradationof thecytoplasmic material insidethe autolysosomes (Fig. 1a). Vesicle nucleation dependscritically on a class III phosphatidylinositol-3-OH kinase(PI3K) Vps34 and other proteins including Beclin-1,Atg14, Vps15, UVRAG, Ambra-1 and Bif-1. The lipidkinase activity of this complex is kept in check by Bcl-2familyofproteinsandalsoinhibitedbymammaliantargetof rapamycin (mTOR). Selective sequestration of toxiccellular waste is dependent on protein markers such asp62, also known as sequestosome-1 (SQSTM1). Vesicleelongation and closure is mediated by two ubiquitin-likeconjugation systems, both employing Atg7 as an E1-likeligase.Atg7andAtg10actinsuccessiontoconjugateAtg5with Atg12. Atg16L1 is assembled with the Atg12-Atg5conjugate.Atg16L1canalsoformahomotetramer,result-ing in a multimer of the Atg12-Atg5-Atg16 complexwhich gets recruited to the initial membrane and servesas an E3 ligase in the lipidation of LC3-1 with phospha-tidylethanolamine. Atg7, in concert with Atg3, act as theE1 and E2-like ligases in this second system. The lipi-dated LC3-PE remains embedded within the lumen ofthe autophagosome, whereas the LC3-PE present on the