Valgerður Hjaltalín and Margrét Helga Ögmundsdóttir
Introduction
Autophagy is a highly conserved degradation pathway which plays a central role in cellular homeostasis, by clearance of detrimental cellular material and supply of building blocks for anabolic reactions. Our study is focused on the autophagy protein ATG7, which is primarily known for its key role in the elongation of the autophagosome membrane by mediating the lipidation of the ATG8 proteins. Previously, we described a novel vertebrate specific region (VSR) within the active domain of ATG7. Interestingly, this region is intrinsically disordered and harbors two sites which have been linked to cancer in humans. While human ATG7 could rescue lipidation in Atg7 null mouse embryonic fibroblasts (MEFs), ATG7 lacking the VSR failed to effectively do so. This indicates that the VSR is important to the function of ATG7 in autophagy.
Methods
We have generated fruit fly models with knockout of fly Atg7 and rescue with human ATG7, with and without the VSR.
Results
Fruit flies are viable without Atg7, but exhibit shortened lifespan, decreased motor function and tolerance to stress. While human ATG7 could rescue ATG8 lipidation in the MEFs, it failed to do so in fruit flies. In fact, the human ATG7 expressing strain performed worse in most aspects of the study. Interestingly, preliminary data suggests that dVSR-ATG7 can rescue lipidation.
Conclusions
The study describes the emergence of a novel region which is indispensable for ATG8 lipidation in mammals, but conversely might disrupt lipidation in fruit flies.
