A retrograde, non-canonical integrated stress response cascade maintains synaptic strength under amino acid deprivation.

Neuronal response to changes in nutrient availability is critical for maintaining metabolic homeostasis and organismal survival. Nevertheless, we know little about the molecular players that regulate and maintain neurotransmission under nutritional stress. We demonstrate that, under acute amino acid restriction, the maintenance of normal synaptic strength at the Drosophila larval neuromuscular junction critically depends on the integrated stress response (ISR) machinery. Our findings indicate that amino acid restriction triggers a non-canonical ISR cascade in muscle via GCN2 and eIF2α phosphorylation but independently of ATF4. We have identified Still life (Sif), an ortholog of human TIAM1, as a translational target of the ISR and show that it is required in muscle for mediating the action of the ISR. Our results reveal an intricate non-canonical ISR signaling cascade at the synapse and offer a new framework to separate the role of the ISR in proteostasis from its synaptic actions.