ABSTRACT: Mitochondrial dysfunction and extracellular protein aggregation occur in neurodegenerative diseases such as Alzheimer’s disease (AD). However, it remains unclear if these processes are functionally linked. Here, we identify a signaling pathway that is activated upon accumulation of aggregation-prone proteins in the extracellular space. We find that the transcription factor ATFS-1, which regulates the mitochondrial unfolded protein response, also regulates transcripts required for endosomal recycling, multiple plasma membrane-localized signaling receptors, and secreted proteins that bind aggregation-prone proteins in the extracellular space, including transthyretin and Aβ, and promote their degradation. Interestingly, Aβ(1-42) aggregation induces atfs-1-dependent transcription by promoting degradation of the bZIP protein ZIP-3, which antagonizes ATFS-1. ZIP-3 accumulates in the cytosol when it is phosphorylated by kinases that function downstream of plasma membrane-localized signaling receptors, including the WNT and glutamate receptors. Upon ligand binding, the signaling receptors stimulate the cognate kinase, many of which we found phosphorylate ZIP-3, impeding ZIP-3 degradation, allowing it to antagonize atfs-1-dependent transcription. However, accumulation of aggregation-prone proteins such as Aβ(1–42) causes endosomal swelling, which impairs endosomal recycling, instead diverting signaling receptors to lysosomes for degradation. In turn, the depletion of signaling receptors reduces the level of ZIP-3 phosphorylation, resulting in ZIP-3 degradation and activation of atfs-1-dependent transcription, which promotes extracellular proteostasis. Similar to ATFS-1, the mammalian homologs ATF4 and ATF5 regulate genes linked to endosomal components, endosomal recycling, and extracellular chaperones, suggesting that the mechanism to mitigate extracellular protein aggregation is evolutionarily conserved. Our findings uncover an unexpected coupling between endocytic quality control and mitochondrial signaling, revealing a circuit that preserves extracellular proteostasis and promotes organismal resilience.
