Autophagy

Autophagy is a protein, macromolecular complex, and organelle degradation process that requires the assembly of a mixed protein/membrane structure (autophagosome) that targets and delivers substrates for degradation in the lysosome as illustrated below. Elegant genetic screens revealed the identify of ~40 integral genes involved in this process, however the mechanistic details of how autophagosomes assemble are still unclear.

autophagy_schematic_v3.png

Interestingly, autophagy was once thought to act nonspecifically, however recent work has found ‘selective’ forms of autophagy specifically targeted at particular organelles, macromolecular complexes, and individual proteins. Notably, the relative importance of selective vs. non-selective autophagy in maintaining proteostasis or in driving pathology is currently underexplored.

The Davis lab is working to uncover autophagosome assembly and maturation pathways, determine the effect of disease-linked mutations on the assembly pathway and to understand how this process might be therapeutically modulated.

Key questions of interest to the Davis lab include:

  • What is the order of protein binding in autophagosome assembly and how do mutations in autophagy proteins affect the assembly pathway?
  • How do post-translational modifications affect assembly kinetics?
  • What are the structures of the assembly intermediates required for autophagosome maturation?
  • What is the full complement of selective autophagic substrates and how quickly are these substrates degraded?
  • How do genetic mutations, environmental stress, or organismal aging affect substrate selection and degradation rates?
  • Which receptor proteins select targets for degradation?