RRC ID 46197
Author Silva MC, Amaral MD, Morimoto RI.
Title Neuronal reprograming of protein homeostasis by calcium-dependent regulation of the heat shock response.
Journal PLoS Genet
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.
Volume 9(8)
Pages e1003711
Published 2013-8-1
DOI 10.1371/journal.pgen.1003711
PMID 24009518
PMC PMC3757039
MeSH Animals Caenorhabditis elegans / genetics* Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Calcium / metabolism Calmodulin / genetics Heat-Shock Response / genetics* Homeostasis / genetics* Humans Molecular Chaperones / metabolism Muscle Cells / metabolism Neuromuscular Junction / genetics* Neurons / metabolism Receptors, Cholinergic / metabolism Signal Transduction Transcription Factors / genetics Transcription Factors / metabolism*
IF 5.175
Times Cited 12
C.elegans tm6548