RRC ID 46429
Author Richard M, Boulin T, Robert VJ, Richmond JE, Bessereau JL.
Title Biosynthesis of ionotropic acetylcholine receptors requires the evolutionarily conserved ER membrane complex.
Journal Proc. Natl. Acad. Sci. U.S.A.
Abstract The number of nicotinic acetylcholine receptors (AChRs) present in the plasma membrane of muscle and neuronal cells is limited by the assembly of individual subunits into mature pentameric receptors. This process is usually inefficient, and a large number of the synthesized subunits are degraded by endoplasmic reticulum (ER)-associated degradation. To identify cellular factors required for the synthesis of AChRs, we performed a genetic screen in the nematode Caenorhabditis elegans for mutants with decreased sensitivity to the cholinergic agonist levamisole. We isolated a partial loss-of-function allele of ER membrane protein complex-6 (emc-6), a previously uncharacterized gene in C. elegans. emc-6 encodes an evolutionarily conserved 111-aa protein with two predicted transmembrane domains. EMC-6 is ubiquitously expressed and localizes to the ER. Partial inhibition of EMC-6 caused decreased expression of heteromeric levamisole-sensitive AChRs by destabilizing unassembled subunits in the ER. Inhibition of emc-6 also reduced the expression of homomeric nicotine-sensitive AChRs and GABAA receptors in C. elegans muscle cells. emc-6 is orthologous to the yeast and human EMC6 genes that code for a component of the recently identified ER membrane complex (EMC). Our data suggest this complex is required for protein folding and is connected to ER-associated degradation. We demonstrated that inactivation of additional EMC members in C. elegans also impaired AChR synthesis and induced the unfolded protein response. These results suggest that the EMC is a component of the ER folding machinery. AChRs might provide a valuable proxy to decipher the function of the EMC further.
Volume 110(11)
Pages E1055-63
Published 2013-3-12
DOI 10.1073/pnas.1216154110
PII 1216154110
PMID 23431131
PMC PMC3600456
MeSH Animals Caenorhabditis elegans / cytology Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Endoplasmic Reticulum / genetics Endoplasmic Reticulum / metabolism* Humans Intracellular Membranes / metabolism* Multiprotein Complexes / genetics Multiprotein Complexes / metabolism* Protein Folding Receptors, Cholinergic / genetics Receptors, Cholinergic / metabolism* Receptors, GABA-A / genetics Receptors, GABA-A / metabolism
IF 9.58
Times Cited 16
C.elegans tm1453