Transcellular chaperone signaling is an intercellular stress-response distinct from the HSF-1 mediated HSR

Abstract

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 C. 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 HSR is switched off upon TCS activation, in favor of an intercellular stress-signaling-route to safeguard survival.

The Intestine as a Lifespan- and Proteostasis-Promoting Signaling Tissue

“…The subsequent muscular HSP-90 upregulation is able to suppress the age-dependent aggregation of amyloid beta (Aβ) in the muscle ( O’Brien et al, 2018 ). Conversely, intestinal hsp-90 knockdown has been found to signal via secreted peptides TXT-4, TXT-8, and TXT-12 to induce the guanylate cyclase TXT-1 and the transcription factor CEH-58 in muscle cells leading to upregulation of hsp-70 which results in an improved survival when exposed to elevated temperatures ( Miles et al, 2022 ). These findings provide evidence that the intestine can be a major regulator of proteostasis and stress resistance through cell nonautonomous regulation of molecular chaperones via transcellular chaperone signaling (TCS) ( Figure 2A ) ( O’Brien et al, 2018 ).…”

HLH-1 Modulates Muscle Proteostasis During Caenorhabditis elegans Larval Development

“…Other transcription factors, such as the heat shock transcription factors (HSFs), regulate chaperones’ expression during development ( Li et al, 2016 ; Li et al, 2017 ) or modulate the muscle heat shock response ( Guisbert et al, 2013 ). Furthermore, trans-cellular signaling modulates chaperone expression in muscle in response to changes in chaperone expression in neurons or intestine cells ( O'Brien et al, 2018 ; Miles et al, 2022 ). Therefore, the chaperone system can be shaped and reshaped during development.…”

Biotic, abiotic and genetic perturbations in genetically variant Caenorhabditis elegans

“…There is no publication on the function of txt-14 and txt does not have an orthologue with human neither. But the expression of txt-14 was reported related to hsf-1-mediated HSR [220]. It can interact with dpy-10 and hsf-1.…”