Autophagy
Autophagy is a process to degrade proteins, macromolecular complexes, and organelles that requires the assembly of a mixed protein/membrane structure (autophagosome). The autophagosome targets and delivers substrates for degradation in the lysosome as illustrated below. Elegant genetic screens revealed the identity of ~40 integral genes involved in this process, however the mechanistic details of how autophagosomes assemble are still unclear.
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: 1) discover novel selective autophagy substrates; 2) uncover autophagosome assembly and maturation pathways; 3) determine how these pathways differ in selective vs. non-selective autophagy; and 4) to measure the effect of disease-linked mutations on the assembly pathways.
Long-term, we hope to probe 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?