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

Abstract Synaptic proteostasis is crucial for maintaining neuronal function and plasticity, yet how synapses adapt to metabolic stress remains poorly understood. Here, we show that nutrient deprivation, particularly serum withdrawal, induces robust autophagy-dependent remodeling of the synaptic proteome, while mTORC1 inhibition has more limited effects. Nutrient stress rapidly activates autophagy both globally and at synapses, with synaptic autophagy peaking within 1–2 hours of serum withdrawal. Mechanistically, we uncover that the LC3 lipidation complex (ATG5–ATG12–ATG16L1) is recruited to synapses via Rab5b-positive endosomes in a dynein-dependent manner. Live imaging reveals enhanced Rab5b–ATG16L1 co-trafficking and increased ATG5 mobility upon serum withdrawal, supporting a model of spatiotemporally controlled autophagy precursor delivery to synaptic compartments. Functionally, nutrient deprivation acutely dampens neuronal excitability in vitro , while a two-week fasting-mimicking diet in vivo triggers synaptic proteome remodeling that overlaps with starvation-induced autophagy cargo. In contrast, restriction of mTORC1-activating amino acids fails to induce comparable synaptic changes, suggesting that synaptic autophagy is regulated by nutrient signals beyond mTORC1. Our findings define a Rab5b-mediated trafficking mechanism that couples nutrient sensing to localized synaptic degradation, providing new insight into how neurons preserve proteostasis under metabolic challenge.