ER chaperones play a major role in cellular homeostasis by regulating the assembly of polypeptides, intracellular Ca2+ signaling, and degradation of misfolded proteins. Here we report on an ER - resident chaperone NRA-2 that modulates hyper-activated ion channel-induced necrosis by regulating surface expression of a death-inducing DEG/ENaC channel family member subunit MEC-10(d).
nra-2 was previously identified in a screen for nicotinic acetylcholine receptor (nAChR) - interacting proteins and was found to regulate the subunit composition of the AChR receptor in C. elegans muscle1. We found that loss of function of
nra-2 led to a significant increase in
mec-10(d) - induced necrosis in C. elegans touch receptor neurons (TRNs), and this enhancement was rescued by TRN-specific transgenic expression of
nra-2. We observed that loss of
nra-2 led to a significant increase in surface localization of MEC-10(d)::GFP and a significant decrease in ER localization. Electrophysiological experiments in Xenopus oocytes revealed that NRA-2 suppresses amiloride-sensitive currents induced by hyperactivated MEC channels. Our study suggests a role for NRA-2 as an ER quality control protein that inhibits surface expression of mutant MEC-10(d) channels and is thus neuroprotective against hyperactivated ion channel-induced necrosis. 1. Ruta B. Almedom, Jana F. Liewald, Guillermina Hernando, Christian Schultheis, Diego Rayes, Jie Pan, Thorsten Schedletzky, Harald Hutter, Cecilia Bouzat, and Alexander Gottschalk. An ER-resident membrane protein complex regulates nicotinic acetylcholine receptor subunit composition at the synapse. The EMBO Journal, 28(17):2636-2649, July 2009.