The heat shock response (HSR) senses protein misfolding in the cell and induces a set of conserved heat shock proteins, many of which help to restore protein homeostasis (proteostasis). The HSR is a cell-autonomous response, but under some conditions, it can be coordinately regulated across tissues and throughout the whole organism. Currently, the distinctions between cell-autonomous and coordinate HSR regulation are not well established.
Previously, we identified a tissue-specific HSR regulatory network in Caenorhabditis elegans. Here, we analyze several of these regulators and uncover mechanisms that drive their tissue-specific HSR regulation. We find that muscle-specific regulation of the HSR by the TRiC/CCT chaperonin complex is not driven by muscle-specific expression of the TRiC/CCT complex itself, but rather by actin, one of its the primary cellular substrates. Actin knockdown reduces the sensitivity of muscle to TRiC/CCT and broad overexpression of an actin isoform expands the tissue-specificity of TRiC/CCT regulation of the HSR by sensitizing intestinal cells. Additionally, we characterized the actin overexpression line and found that it has several interesting phenotypes, including shortened lifespan, supporting other recent research suggesting that maintenance of the actin cytoskeleton is an important factor for maintaining longevity. Futhermore, we show that intestine-specific regulation of the HSR by components of the secretory pathway is driven by the vitellogenins, some of the major secreted proteins in the intestine.
Together, these data reveal that tissue-specific regulation of the HSR reflects a balance between the protein homeostasis (proteostasis) machinery and the specific requirements arising from the cellular proteome. This tissue-specific regulatory mechanism is similar to the well-established regulation of the HSR by the HSP70 and HSP90 chaperones that is also dependent on their cellular substrates but is not tissue-specific. Our findings that distinct cellular proteomes influence HSR regulation have important implications because the HSR has been implicated in a variety of tissue-specific diseases including cancers and neurodegenerative diseases.