Targeting DNAJB9, a novel ER luminal co-chaperone, to rescue ΔF508-CFTR

Sci Rep. 2019 Jul 8;9(1):9808. doi: 10.1038/s41598-019-46161-4.


The molecular mechanism of Endoplasmic Reticulum-associated degradation (ERAD) of Cystic fibrosis transmembrane-conductance regulator (CFTR) is largely unknown. Particularly, it is unknown what ER luminal factor(s) are involved in ERAD. Herein, we used ProtoArray to identify an ER luminal co-chaperone, DNAJB9, which can directly interact with CFTR. For both WT- and ΔF508 (deletion of phenylalanine at position 508, the most common CF-causing mutant)-CFTR, knockdown of DNAJB9 by siRNA increased their expression levels on the cell surface and, consequently, upregulated their function. Furthermore, genetic ablation of DNAJB9 in WT mice increased CFTR expression and enhanced CFTR-dependent fluid secretion in enteroids. Importantly, DNAJB9 deficiency upregulated enteroids' fluid secretion in CF mice (homozygous for ΔF508), and silencing one allele of DNAJB9 is sufficient to rescue ΔF508-CFTR in vitro and in vivo, suggesting that DNAJB9 may be a rate-limiting factor in CFTR ERAD pathway. Our studies identified the first ER luminal co-chaperone involved in CFTR ERAD, and DNAJB9 could be a novel therapeutic target for CF.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Endoplasmic Reticulum-Associated Degradation
  • Gene Knockdown Techniques
  • HEK293 Cells
  • HSP40 Heat-Shock Proteins / genetics*
  • HSP40 Heat-Shock Proteins / metabolism*
  • Humans
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Mice
  • Molecular Chaperones / genetics*
  • Molecular Chaperones / metabolism*
  • Protein Array Analysis
  • Sequence Deletion*


  • CFTR protein, human
  • DNAJB9 protein, human
  • HSP40 Heat-Shock Proteins
  • Membrane Proteins
  • Molecular Chaperones
  • Cystic Fibrosis Transmembrane Conductance Regulator