The Hsp90‐dependent and Indepedent roles of FKBP38 in the biogenesis of CFTR

Abstract

The cellular chaperone machinery regulates the biogenesis of nascent ion channels such as the cystic fibrosis transmembrane conductance regulator (CFTR). FK506‐binding protein 38 (FKBP38), an immunophilin anchored to the endoplasmic reticulum (ER) membrane, was identified as a component of a chaperone network associated with CFTR in the ER. Like FKBP52, FKBP38 binds Hsp90 through its tetratricopeptide repeat (TPR) domain. FKBP52 serves as an Hsp90 cochaperone in the activation of steroid receptors. However, the functional relationship between FKBP38 and Hsp90 in the context of CFTR biogenesis remains unclear. To understand the regulation of CFTR biogenesis by FKBP38, we introduced a series of domain‐specific, shRNA‐refractory mutants of FKBP38 into an FKBP38‐deficient cell line. Our data support a central role for the peptidylprolyl cis/trans isomerase in FKBP38‐mediated folding of CFTR and a moderate regulatory role for Hsp90 in FKBP38‐mediated folding and/or quality control of CFTR in the ER.