Neuronal signaling modulates protein homeostasis in Caenorhabditis elegans post-synaptic muscle cells.
Protein homeostasis maintains proper intracellular balance by promoting protein folding and clearance mechanisms while minimizing the stress caused by the accumulation of misfolded and damaged proteins. Chronic expression of aggregation-prone proteins is deleterious to the cell and has been linked to a wide range of conformational disorders. The molecular response to misfolded proteins is highly conserved and generally studied as a cell-autonomous process. Here, we provide evidence that neuronal signaling is an important modulator of protein homeostasis in post-synaptic muscle cells. In a forward genetic screen in Caenorhabditis elegans for enhancers of polyglutamine aggregation in muscle cells, we identified unc-30, a neuron-specific transcription factor that regulates the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). We used additional sensors of protein conformational states to show that defective GABA signaling or increased acetylcholine (ACh) signaling causes a general imbalance in protein homeostasis in post-synaptic muscle cells. Moreover, exposure to GABA antagonists or ACh agonists has a similar effect, which reveals that toxins that act at the neuromuscular junction are potent modifiers of protein conformational disorders. These results demonstrate the importance of intercellular communication in intracellular homeostasis.
Garcia
Susana M
SM
Department of Biochemistry, Molecular Biology and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208, USA.
Casanueva
M Olivia
MO
Silva
M Catarina
MC
Amaral
Margarida D
MD
Morimoto
Richard I
RI
D000109:Acetylcholine / Q000819:agonists; D000483:Alleles; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D005020:Ethyl Methanesulfonate / Q000633:toxicity; D016650:Fluorescein-5-isothiocyanate; D019084:Fluorescent Antibody Technique, Indirect; D005456:Fluorescent Dyes; D018756:GABA Antagonists / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D009046:Motor Neurons / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009153:Mutagens / Q000633:toxicity; D009469:Neuromuscular Junction / Q000378:metabolism / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000502:physiology*; D015398:Signal Transduction; D013569:Synapses; D019076:Transgenes; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis
D029742:Caenorhabditis elegans Proteins; D005456:Fluorescent Dyes; D018756:GABA Antagonists; D018398:Homeodomain Proteins; D009124:Muscle Proteins; D009153:Mutagens; D009687:Nuclear Proteins; D011506:Proteins; C090946:unc-30 protein, C elegans; D005680:gamma-Aminobutyric Acid; D005020:Ethyl Methanesulfonate; D016650:Fluorescein-5-isothiocyanate; D000109:Acetylcholine