Endolysosomal processing of neuron-derived signaling lipids regulates autophagy and lipid droplet degradation in astrocytes

Astrocytes support brain metabolism by processing, storing, and appropriating metabolites. Dynamic regulation of metabolic activities in astrocytes is critical to meeting the demands of other brain cells. During neuronal stress, lipid metabolites are transferred from neurons to astrocytes, where they are stored in lipid droplets (LDs). However, it is not clear whether and how neuron-derived lipids trigger metabolic adaptation in astrocytes. Here, we uncover an endolysosomal function that mediates a neuron-astrocyte transcellular lipid signaling paradigm. We identify Tweety homolog 1 (TTYH1) as an astrocyte-enriched transmembrane protein localized to endolysosomes, where it facilitates autophagic flux and lipid droplet (LD) degradation. Astrocyte-specific deletion of Ttyh1 in mice and loss of TTYH1 ortholog in Drosophila lead to brain accumulation of neutral lipids. Computational and experimental evidence suggests that TTYH1 mediates endolysosomal clearance of ceramide 1-phosphate (C1P), a sphingolipid that dampens autophagic flux and LD breakdown in mouse and human astrocytes. We found that the inflammatory cytokine IL-1β induces neuronal upregulation of C1P biosynthesis. Concurrently, lipids secreted by neurons cause autophagic flux impairment and LD accumulation in astrocytes. Whereas TTYH1 deficiency in astrocytes exacerbates the catabolic blockage, inhibiting C1P synthesis in neurons restores autophagic flux and normalizes LD contents in astrocytes. Thus, astrocytes rely on the endolysosomal function of TTYH1 to mitigate the metabolic effects of neuron-derived lipids. Taken together, our findings reveal a neuron-initiated signaling paradigm that culminates in the regulation of catabolic activities in astrocytes.