title: Cellular Proteomes Drive Tissue-Specific Regulation of the Heat Shock Response.
abstract: The heat shock response (HSR) is a cellular stress response that senses protein misfolding and restores protein folding homeostasis, or proteostasis. We previously identified an HSR regulatory network inCaenorhabditis elegansconsisting of highly conserved genes that have important cellular roles in maintaining proteostasis. Unexpectedly, the effects of these genes on the HSR are distinctly tissue-specific. Here, we explore this apparent discrepancy and find that muscle-specific regulation of the HSR by the TRiC/CCT chaperonin is not driven by an enrichment of TRiC/CCT in muscle, but rather by the levels of one of its most abundant substrates, actin. Knockdown of actin subunits reduces induction of the HSR in muscle upon TRiC/CCT knockdown; conversely, overexpression of an actin subunit sensitizes the intestine so that it induces the HSR upon TRiC/CCT knockdown. Similarly, intestine-specific HSR regulation by the signal recognition particle (SRP), a component of the secretory pathway, is driven by the vitellogenins, some of the most abundant secretory proteins. Together, these data indicate that the specific protein folding requirements from the unique cellular proteomes sensitizes each tissue to disruption of distinct subsets of the proteostasis network. These findings are relevant for tissue-specific, HSR-associated human diseases such as cancer and neurodegenerative diseases. Additionally, we characterize organismal phenotypes of actin overexpression including a shortened lifespan, supporting a recent hypothesis that maintenance of the actin cytoskeleton is an important factor for longevity.
authors.affiliation: Department of Biological Sciences, Florida Institute of Technology, Melbourne, Florida 32901.
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Biological Sciences, Florida Institute of Technology, Melbourne, Florida 32901.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Grant
authors.affiliation: Department of Biological Sciences, Florida Institute of Technology, Melbourne, Florida 32901.
authors.forename: Rosemary N
authors.initials: RN
authors.lastname: Plagens
authors.affiliation: Department of Biological Sciences, Florida Institute of Technology, Melbourne, Florida 32901.
authors.forename: Lindsey N
authors.initials: LN
authors.lastname: Barrett
authors.affiliation: Department of Biological Sciences, Florida Institute of Technology, Melbourne, Florida 32901.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Kim Guisbert
authors.affiliation: Department of Biological Sciences, Florida Institute of Technology, Melbourne, Florida 32901 eguisbert@fit.edu.
authors.forename: Eric
authors.identifier: 0000-0003-1901-5598
authors.initials: E
authors.lastname: Guisbert
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D018869:Heat-Shock Response; D007413:Intestinal Mucosa / Q000378:metabolism; D008954:Models, Biological; D009132:Muscles / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D010641:Phenotype; D021122:Protein Subunits / Q000378:metabolism; D020543:Proteome / Q000378:metabolism*; D014819:Vitellogenins / Q000378:metabolism
chemical_list: D000199:Actins; D029742:Caenorhabditis elegans Proteins; D021122:Protein Subunits; D020543:Proteome; D014819:Vitellogenins
keywords: HSF1; heat shock response; protein folding; proteostasis; stress response