The ER Lumenal Chaperone, Lhs1/GRP170, Plays a Unique Role in the Degradation of the Epithelial Sodium Channel

Abstract

The Epithelial Sodium Channel (ENaC) is composed of three homologous subunits – α, β, and γ – that assemble in the endoplasmic reticulum (ER) to form the mature ENaC channel. However, channel maturation is inefficient, thus targeting the channel subunits for Endoplasmic Reticulum Associated Degradation (ERAD). To characterize the ENaC degradation pathway, a yeast ENaC expression system was developed. Using this system, we found that Jem1 and Scj1, two ER lumenal Hsp40 chaperones, play a role in ENaC degradation. Jem1 and Scj1 act as cochaperones for the ER lumenal Hsp70, BiP, but, surprisingly BiP does not play a role in ENaC degradation. Therefore, we hypothesized that another ER chaperone with an Hsp70‐like domain, Lhs1, may be involved. We found that Lhs1 facilitates αENaC subunit degradation, but that Lhs1 ATPase activity is dispensable for ENaC degradation. This result further supports our conclusion that the BiP cochaperones are acting in a BiP independent fashion. Our data also indicate the human Lhs1 homolog, GRP170, affects ENaC biogenesis in an oocyte system. In conclusion, we have identified a new ER chaperone as a novel effector of αENaC biogenesis. Funded in part by K01: DK090195.