In metazoans, tissues experiencing proteotoxic stress induce “transcellular chaperone signaling” (TCS) that activates molecular chaperones, such as hsp-90, in distal tissues. How this form of inter-tissue communication is mediated to upregulate systemic chaperone expression and whether it can be utilized to protect against protein misfolding diseases remain open questions. Using C. elegans, we identified key components of a systemic stress signaling pathway that links the innate immune response with proteostasis maintenance. We show that mild perturbation of proteostasis in the neurons or the intestine activates TCS via the GATA zinc-finger transcription factor PQM-1. PQM-1 coordinates neuron-activated TCS via the innate immunity-associated transmembrane protein CLEC-41, whereas intestine-activated TCS depends on the aspartic protease ASP-12. Both TCS pathways can induce hsp-90 in muscle cells and facilitate amelioration of Aβ3-42-associated toxicity. This may have powerful implications for the treatment of diseases related to proteostasis dysfunction. Display omitted •PQM-1 is activated in the neurons or gut to induce TCS-mediated hsp-90 expression•Neuron-induced TCS is mediated via PQM-1/CLEC-41 signaling•Intestine-induced TCS is mediated via PQM-1/ASP-12 signaling•TCS via PQM-1 is required for proteostasis and reduces amyloid beta misfolding O’Brien et al. find that the GATA transcription factor PQM-1 functions as a mediator of transcellular chaperone signaling (TCS). Depending on the sender tissue, PQM-1 activates a neuron-specific or intestine-specific TCS route that triggers hsp-90 expression in remote tissues. TCS-mediated hsp-90 induction reduces amyloid beta oligomerization and toxicity.