SummaryIn 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.

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Maintenance of organismal proteostasis requires the coordination of protein quality control responses such as chaperone expression from one tissue to another. Here, we provide tools used in C. elegans that allow monitoring of proteostasis capacity in specific tissues and determine intercellular signaling responses. ABSTRACT: Over the past decade, regulation of protein quality control processes went through a transformation that unveiled the importance of intercellular signaling processes to regulate cellnonautonomous proteostasis. Recent studies are now beginning to uncover signaling components and pathways that coordinate protein quality control from one tissue to another. It is therefore important to identify mechanisms and components of the cell-nonautonomous proteostasis network (PN) and its relevance for aging, stress responses and protein misfolding diseases. In the laboratory, we use genetic knockdown by tissue-specific RNAi in combination with stress reporters and tissue-specific proteostasis sensors. We describe methodologies to examine and to identify components of the cell-nonautonomous PN that can act in tissues perceiving a stress condition and in responding cells to activate a protective response. We first describe how to generate hairpin RNAi constructs for constitutive genetic knockdown in specific tissues and how to perform tissue-specific genetic knockdown by feeding RNAi at different life stages. Stress reporters, and behavioral assays then function as a valuable readout, that allow for the fast screening of genes and conditions modifying systemic stress signaling processes. Finally, proteostasis sensors expressed in different tissues are utilized to determine changes in the tissuespecific capacity of the PN at different stages of development and aging. Thus, these tools should help clarify and allow monitoring the capacity of PN in specific tissues, while helping to identify components that function in different tissues to mediate cell-nonautonomous PN in an organism. INTRODUCTION: Cellular proteostasis is monitored by an intricate network of protein quality control components such as molecular chaperones, stress responses and degradation mechanisms including the ubiquitin proteasome system (UPS) and autophagy 1,2. The activation of stress response pathways, such as the HSF-1 mediated heat shock response (HSR), the unfolded protein response of the endoplasmic reticulum (UPR ER) and the mitochondria (UPR mito) is vital for cellular adaptation to and survival during environmental challenges or protein misfolding disease that lead to toxic protein aggregation 1-6. Cellular proteostasis is coordinated by an additional layer in multicellular organisms that requires the orchestration of cellular stress responses across different tissues to activate protective protein quality control components such as molecular chaperones 7. In the past decade, cell nonautonomous activation of "cellular" stress response pathways has been observed for the heat shock response (HSR), the UPR ER and the UPR mito , as we...