Impaired endosomal recycling of signaling receptors activates an extracellular UPR

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.