Autophagy: regulation and role in development

Abstract

Autophagy is an evolutionarily conserved cellular process through which long-lived proteins and damaged organelles are recycled to maintain energy homeostasis. These proteins and organelles are sequestered into a double-membrane structure, or autophagosome, which subsequently fuses with a lysosome in order to degrade the cargo. Although originally classified as a type of programmed cell death, autophagy is more widely viewed as a basic cell survival mechanism to combat environmental stressors. Autophagy genes were initially identified in yeast and were found to be necessary to circumvent nutrient stress and starvation. Subsequent elucidation of mammalian gene counterparts has highlighted the importance of this process to normal development. This review provides an overview of autophagy, the types of autophagy, its regulation and its known impact on development gleaned primarily from murine models.

Keywords: autophagy; development; knockout models; regulation.

Figure 1. The core machinery of autophagy. Autophagy is a complex degradation process in which general cytoplasm or organelles are engulfed by a double-membrane bound structure and degraded and recycled following fusion with a lysosome. (A) Dephosphorylated ULK1 dissociates from the MTOR complex and phosphorylates itself, ATG13 and RB1CC1 to induce the nucleation phase. (B) The PtdIns3K complex is assembled at the site of the nascent autophagosomal membrane. UVRAG and ATG14 are found in BECN1 complexes in a mutually exclusive manner. BECN1 is inhibited when bound by anti-apoptotic BCL2, which results in downregulated autophagy. (C) The two ubiquitin-like conjugation systems essential for membrane elongation are outlined schematically. (D) The autophagosomal membrane (orange crescent) is studded with LC3–PE (stylized in black). The membrane elongation is dependent on the ATG12–ATG5-ATG16L1 conjugation system. During fusion with the lysosome (blue oval) LC3–PE associated with the outer membrane is cleaved and recycled by ATG4 while LC3–PE associated with the inner-membrane is degraded by lysosomal proteases along with the cargo of the autophagosome.