Autophagy plays a surprisingly constructive role in Drosophila synapse development, counteracting a proteasome-mediated degradation pathway, say Shen and Ganetzky.
The E3 ubiquitin ligase Highwire (Hiw) limits neuromuscular junction (NMJ) growth presumably by sending proteins to their destruction at the hands of the proteasome. Shen and Ganetzky wondered whether protein degradation by autophagosomes might similarly regulate NMJ development.
Flies with impaired autophagy had smaller NMJs than wild-type flies, whereas overexpressing an inducer of autophagy called Atg1 caused NMJ overgrowth. Activating autophagy by feeding larvae with rapamycin also enlarged NMJs, indicating that the degradative pathway promotes rather than inhibits synaptic development. The supersized NMJs of flies overexpressing Atg1 were remarkably similar to those of hiw mutants, leading the authors to investigate whether the two pathways were linked. Hiw protein levels were reduced upon autophagy induction, while boosting levels of the ubiquitin ligase reversed the NMJ overgrowth induced by Atg1. Autophagy therefore promotes synaptogenesis by degrading Hiw and blocking its inhibitory effects.
Although it is usually thought of as a nonspecific catchall for protein destruction, there are a few examples where autophagy is more discriminating in its function. The authors therefore want to determine whether Hiw is specifically targeted for destruction by autophagosomes and, if so, how the process occurs. They point out that autophagy is ideally suited to regulating synaptic growth and remodeling because the pathway responds to a wide range of environmental cues.