De novo synthesis of phospholipids is coupled with autophagosome formation

Autophagy, the process involved in the breakdown of intracellular proteins and organelles, has become an area of great importance in both cell survival and cell death. Despite the abundance of information on this topic, persisting issues remain about the origin and mechanism of formation of the autophagosomal membrane. The endoplasmic reticulum (ER) plays a critical role in the initiation of autophagy, especially in the formation of early lipid particles, termed the phagophores or the isolation membranes. The bulk, if not all of the lipid biosynthetic pathways cease at the level of the ER where the main synthesizing enzymes are resident proteins. We postulate that if the initial isolation membrane is formed from the locally synthesized lipids at the level of the ER, than an increase in the biosynthesis of the bilayer-forming phospholipids (phosphatidylcholine-PC, phosphatidylethanolamine-PE, and phosphatidylserine-PS) would occur simultaneously with induction of autophagy. As part of the isolation membranes, PE conjugates the cytosolic microtubule-associated protein 1 light chain 3 (LC3-I), to form LC3-II, the selective autophagosomal protein. Phosphatidylinositol-3-kinase (PI3K) action on the ER phosphatidylinositol occurs with phospholipid biogenesis, and together they act to contribute to the elongation and assembly of the autophagosomal particle.