Mechanisms of Autophagy Initiation

Annu Rev Biochem. 2017 Jun 20;86:225-244. doi: 10.1146/annurev-biochem-061516-044820. Epub 2017 Mar 15.

Abstract

Autophagy is the process of cellular self-eating by a double-membrane organelle, the autophagosome. A range of signaling processes converge on two protein complexes to initiate autophagy: the ULK1 (unc51-like autophagy activating kinase 1) protein kinase complex and the PI3KC3-C1 (class III phosphatidylinositol 3-kinase complex I) lipid kinase complex. Some 90% of the mass of these large protein complexes consists of noncatalytic domains and subunits, and the ULK1 complex has essential noncatalytic activities. Structural studies of these complexes have shed increasing light on the regulation of their catalytic and noncatalytic activities in autophagy initiation. The autophagosome is thought to nucleate from vesicles containing the integral membrane protein Atg9 (autophagy-related 9), COPII (coat protein complex II) vesicles, and possibly other sources. In the wake of reconstitution and super-resolution imaging studies, we are beginning to understand how the ULK1 and PI3KC3-C1 complexes might coordinate the nucleation and fusion of Atg9 and COPII vesicles at the start of autophagosome biogenesis.

Keywords: Atg1; COPII; ULK1; Vps34; membrane fusion; membrane remodeling; nanoscale biology; phosphatidylinositol 3-kinase; tethering complex; vesicle.

Publication types

  • Review
  • Research Support, N.I.H., Extramural

MeSH terms

  • Autophagy / genetics*
  • Autophagy-Related Protein-1 Homolog / chemistry
  • Autophagy-Related Protein-1 Homolog / genetics
  • Autophagy-Related Protein-1 Homolog / metabolism*
  • COP-Coated Vesicles / metabolism
  • COP-Coated Vesicles / ultrastructure
  • Cell Membrane / metabolism
  • Cell Membrane / ultrastructure
  • Class III Phosphatidylinositol 3-Kinases / chemistry
  • Class III Phosphatidylinositol 3-Kinases / genetics
  • Class III Phosphatidylinositol 3-Kinases / metabolism*
  • Eukaryotic Cells / metabolism
  • Eukaryotic Cells / ultrastructure
  • Gene Expression
  • Gene Expression Regulation
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Phagosomes / metabolism*
  • Phagosomes / ultrastructure
  • Phosphatidylinositol 3-Kinase / chemistry
  • Phosphatidylinositol 3-Kinase / genetics
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Protein Binding
  • Protein Multimerization
  • Signal Transduction

Substances

  • Intracellular Signaling Peptides and Proteins
  • Class III Phosphatidylinositol 3-Kinases
  • Phosphatidylinositol 3-Kinase
  • Autophagy-Related Protein-1 Homolog
  • ULK1 protein, human