Nutrient stress activates RAB5B-mediated autophagy to remodel the synaptic proteome.

Synaptic proteostasis is crucial for neuronal function, yet how synapses adapt to metabolic stress remains unclear. We show that nutrient stress, particularly serum withdrawal, induces autophagy-dependent remodeling of the synaptic proteome, whereas mTORC1 inhibition produces limited effects. Nutrient stress activates synaptic autophagy within 1-2 h and promotes the recruitment of the LC3 lipidation machinery via RAB5B-positive endosomal compartments in a dynein-dependent manner. Live imaging reveals enhanced RAB5B-ATG16L1 co-trafficking and increased ATG5 mobility upon serum withdrawal, indicating spatiotemporally controlled delivery of autophagy precursors to synaptic compartments. Functionally, nutrient deprivation dampens neuronal activity, while a fasting-mimicking diet induces synaptic proteome remodeling overlapping with starvation-associated autophagy cargo. In contrast, restriction of mTORC1-activating amino acids fails to induce comparable remodeling. Together, these findings identify a RAB5B-mediated trafficking pathway that links nutrient sensing to synaptic degradation, revealing how neurons maintain proteostasis under metabolic challenge.