title: Neuronal reprograming of protein homeostasis by calcium-dependent regulation of the heat shock response.
abstract: Protein quality control requires constant surveillance to prevent misfolding, aggregation, and loss of cellular function. There is increasing evidence in metazoans that communication between cells has an important role to ensure organismal health and to prevent stressed cells and tissues from compromising lifespan. Here, we show in C. elegans that a moderate increase in physiological cholinergic signaling at the neuromuscular junction (NMJ) induces the calcium (Ca(2+))-dependent activation of HSF-1 in post-synaptic muscle cells, resulting in suppression of protein misfolding. This protective effect on muscle cell protein homeostasis was identified in an unbiased genome-wide screening for modifiers of protein aggregation, and is triggered by downregulation of gei-11, a Myb-family factor and proposed regulator of the L-type acetylcholine receptor (AChR). This, in-turn, activates the voltage-gated Ca(2+) channel, EGL-19, and the sarcoplasmic reticulum ryanodine receptor in response to acetylcholine signaling. The release of calcium into the cytoplasm of muscle cells activates Ca(2+)-dependent kinases and induces HSF-1-dependent expression of cytoplasmic chaperones, which suppress misfolding of metastable proteins and stabilize the folding environment of muscle cells. This demonstrates that the heat shock response (HSR) can be activated in muscle cells by neuronal signaling across the NMJ to protect proteome health.
authors.affiliation: Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois, United States of America.
authors.forename: M Catarina
authors.initials: MC
authors.lastname: Silva
authors.forename: Margarida D
authors.initials: MD
authors.lastname: Amaral
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000235:genetics; D018869:Heat-Shock Response / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D032342:Muscle Cells / Q000378:metabolism; D009469:Neuromuscular Junction / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D002147:Calmodulin; D018832:Molecular Chaperones; D011950:Receptors, Cholinergic; D014157:Transcription Factors; C474710:heat shock factor-1, C elegans; D002118:Calcium