Transcellular chaperone signaling is an intercellular stress-response distinct from the HSF-1-mediated heat shock response.
Jay MilesSarah TownendDovilė MilonaitytėWilliam SmithFrancesca HodgeDavid R WestheadPatricija van Oosten HawlePublished in: PLoS biology (2023)
Organismal proteostasis is maintained by intercellular signaling processes including cell nonautonomous stress responses such as transcellular chaperone signaling (TCS). When TCS is activated upon tissue-specific knockdown of hsp-90 in the Caenorhabditis elegans intestine, heat-inducible hsp-70 is induced in muscle cells at the permissive temperature resulting in increased heat stress resistance and lifespan extension. However, our understanding of the molecular mechanism and signaling factors mediating transcellular activation of hsp-70 expression from one tissue to another is still in its infancy. Here, we conducted a combinatorial approach using transcriptome RNA-Seq profiling and a forward genetic mutagenesis screen to elucidate how stress signaling from the intestine to the muscle is regulated. We find that the TCS-mediated "gut-to-muscle" induction of hsp-70 expression is suppressed by HSF-1 and instead relies on transcellular-X-cross-tissue (txt) genes. We identify a key role for the PDZ-domain guanylate cyclase txt-1 and the homeobox transcription factor ceh-58 as signaling hubs in the stress receiving muscle cells to initiate hsp-70 expression and facilitate TCS-mediated heat stress resistance and lifespan extension. Our results provide a new view on cell-nonautonomous regulation of "inter-tissue" stress responses in an organism that highlight a key role for the gut. Our data suggest that the HSF-1-mediated heat shock response is switched off upon TCS activation, in favor of an intercellular stress-signaling route to safeguard survival.
Keyphrases
- heat shock
- heat stress
- heat shock protein
- single cell
- rna seq
- transcription factor
- poor prognosis
- skeletal muscle
- genome wide
- oxidative stress
- gene expression
- stem cells
- bone marrow
- high throughput
- cell adhesion
- mesenchymal stem cells
- endothelial cells
- artificial intelligence
- machine learning
- cell therapy
- binding protein
- signaling pathway
- copy number
- long non coding rna
- dna binding
- pi k akt