Cells maintain protein homeostasis (proteostasis) using a network of protein chaperones, folding factors and degradation and signalling components, which respond to cues from the environment. Although this 'proteostasis network' differs between distinct cells types with different requirements, two studies reveal that in Caenorhabditis elegans it can be activated between tissues to promote stress resistance and organismal survival.

Morimoto and colleagues sought to determine whether perturbations in one tissue in C. elegans have an effect on the activation of the heat shock response (HSR) in an adjacent tissue. To this end, they examined the effects of expression of a temperature-sensitive mutant myosin heavy chain B (UNC-54), a muscle-specific client protein of the C. elegans HSP90 homologue. HSP90 mRNA levels were increased twofold in mutant C. elegans compared with wild type; interestingly, HSP90 mRNA levels were also increased in tissues that do not express UNC-54 such as the intestine, indicative of a systemic response. Consistent with this, increased expression of HSP90 in the intestine or neurons suppressed muscle degeneration in UNC-54 mutants by promoting UNC-54 folding and muscle function, similarly to muscle-specific HSP90 expression.

Notably, increased tissue-specific expression of HSP90 suppressed the systemic HSR by blocking activation of the master HSR transcriptional regulator heat shock transcription factor 1 (HSF-1). Indeed, HSP90-overexpressing C. elegans showed reduced expression of the C. elegans homologue of another chaperone, HSP70, in numerous tissues, indicative of a dampened HSR. Moreover, decreasing HSP90 levels in a specific tissue (for example, the body wall muscle) induced the upregulation of HSP70 in the same tissue as well as in other, distal tissues (for example, the intestine and pharynx). Thus, an imbalance in HSP90 levels in one tissue activates a systemic response that modulates the HSR in the whole organism.

Taylor and Dillin focused on the unfolded protein response (UPR), which is activated in the presence of misfolded proteins in the endoplasmic reticulum (ER) and becomes attenuated with age. While examining whether restoring the UPR might enhance lifespan, they found that expression of the UPR protein X box-binding protein 1 (XBP-1) in neurons resulted in UPR activation not only in this tissue but also in the intestine. Moreover, activation of the UPR in the intestine following neuronal XBP-1 activation required an intact intestinal cell UPR, as knockdown of XBP-1 or mutation of inositol-requiring protein 1 (IRE-1; another UPR component) abolished non-cell-autonomous UPR activation. Notably, non-cell-autonomous activation of the UPR promoted stress resistance and extended longevity in C. elegans.

Credit: Artville/Barton Stabler

So, how is this information transmitted between cell types? Morimoto and colleagues found that HSP90 non-cell-autonomous expression depends on the proteostasis protein PHA-4 (defective pharnyx development 4): PHA-4 activity was increased in the tissue experiencing an imbalanced proteostasis network (increased levels of HSP90), which influenced PHA-4 activity (but not its expression) in distal tissues, leading to a coordinated expression of HSP90 in multiple tissues and consequent HSR inhibition. Further work is now needed to elucidate the molecular details of this intercellular chaperone signalling pathway.

Taylor and Dillin postulated that a neuroendocrine system might be involved in transmitting information about the UPR status from neurons to the intestine. Indeed, mutation of UNC-13, which leads to defective release of SCVs, which carry neurotransmitters, resulted in reduced activation of the UPR in the intestine; the identity of the neurotransmitter involved remains to be determined. Furthermore, UNC-13 was necessary for stress resistance and lifespan extension that result from non-cell-autonomous UPR activation.

Together, the two studies provide evidence for the systemic regulation of proteostasis, which presumably ensures the protection of whole organisms from proteotoxic stress.