Autophagosome biogenesis and human health

Abstract

Autophagy degrades the cytoplasmic contents engulfed by autophagosomes. Besides providing energy and building blocks during starvation via random degradation, autophagy selectively targets cytotoxic components to prevent a wide range of diseases. This preventive activity of autophagy is supported by many studies using animal models and reports identifying several mutations in autophagy-related genes that are associated with human genetic disorders, which have been published in the past decade. Here, we summarize the molecular mechanisms of autophagosome biogenesis involving the proteins responsible for these genetic disorders, demonstrating a role for autophagy in human health. These findings will help elucidate the underlying mechanisms of autophagy-related diseases and develop future medications.

Keywords: Macroautophagy; Protein quality control.

Fig. 1. A brief overview of autophagy.

Upon cues such as a starvation signal, isolation membranes are generated de novo that extend to form autophagosomes sequestering cytoplasmic components. The contents are further digested by fusion with lysosomes containing a variety of hydrolases.

Fig. 2. Multiple proteins involved in autophagosome biogenesis are responsible for the suppression of human hereditary disorders involving neurodegeneration.

The formation of the isolation membrane is initiated at the contact sites of the mitochondria and the ER, followed by elongation of the membrane in a structure called the omegasome. PI3P production by PI3K facilitates the recruitment of WIPI2 that further promotes localization of ATG16 at isolation membranes for subsequent modification of LC3. WIPI4 also binds to PI3P to facilitate autophagosome biogenesis via binding to ATG2A, supporting the retention of the omegasome with the ER or a feeding of lipid to isolation membrane.

Fig. 3. Two regulators of autohagosome–lysosome fusion, EPG5 and INPP5E, are responsible for human hereditary disorders.

EPG5, which is responsible for Vici syndrome, is required for the tethering and fusion of autophagosomes and lysosomes. EPG5 facilitates the tethering by direct binding to and assembly of the SNARE complexes composed of STX17, SNAP29 and VAMP8. Jourbert syndrome patients have a mutation the in INPP5E gene. Its gene product INPP5E, a phosphatase, catalyzes the conversion of PI3P to PI(3, 5)P2 on lysosomes, resulting in of the binding of cortactin to actin filaments to stabilize this structure.