Regulation of CLC-1 chloride channel biosynthesis by FKBP8 and Hsp90?.

ABSTRACT: Mutations in human CLC-1 chloride channel are associated with the skeletal muscle disorder myotonia congenita. The disease-causing mutant A531V manifests enhanced proteasomal degradation of CLC-1. We recently found that CLC-1 degradation is mediated by cullin 4 ubiquitin ligase complex. It is currently unclear how quality control and protein degradation systems coordinate with each other to process the biosynthesis of CLC-1. Herein we aim to ascertain the molecular nature of the protein quality control system for CLC-1. We identified three CLC-1-interacting proteins that are well-known heat shock protein 90 (Hsp90)-associated co-chaperones: FK506-binding protein 8 (FKBP8), activator of Hsp90 ATPase homolog 1 (Aha1), and Hsp70/Hsp90 organizing protein (HOP). These co-chaperones promote both the protein level and the functional expression of CLC-1 wild-type and A531V mutant. CLC-1 biosynthesis is also facilitated by the molecular chaperones Hsc70 and Hsp90?. The protein stability of CLC-1 is notably increased by FKBP8 and the Hsp90? inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) that substantially suppresses cullin 4 expression. We further confirmed that cullin 4 may interact with Hsp90? and FKBP8. Our data are consistent with the idea that FKBP8 and Hsp90? play an essential role in the late phase of CLC-1 quality control by dynamically coordinating protein folding and degradation.

SUBMITTER: Peng YJ 

PROVIDER: S-EPMC5007535 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature