The HSP70 co-chaperone DNAJC14 targets misfolded pendrin for unconventional protein secretion

Jinsei Jung, Jiyoon Kim, Shin Hye Roh, Ikhyun Jun, Robert D. Sampson, Heon Yung Gee, Jae Young Choi, Min Goo Lee

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Mutations in SLC26A4, which encodes pendrin, are responsible for hearing loss with an enlarged vestibular aqueduct and Pendred syndrome. The most prevalent mutation in East Asia is p.H723R (His723Arg), which leads to defects in protein folding and cell-surface expression. Here we show that H723R-pendrin can be rescued to the cell surface by an HSP70 co-chaperone DNAJC14-dependent unconventional trafficking pathway. Blockade of ER-to-Golgi transport or activation of ER stress signals induced Golgi-independent cell-surface expression of H723R-pendrin and restored its cell-surface Cl - /HCO 3 - exchange activity. Proteomic and short interfering RNA screenings with subsequent molecular analyses showed that Hsc70 and DNAJC14 are required for the unconventional trafficking of H723R-pendrin. Moreover, DNAJC14 upregulation was able to induce the unconventional cell-surface expression of H723R-pendrin. These results indicate that Hsc70 and DNAJC14 play central roles in ER stress-associated unconventional protein secretion and are potential therapeutic targets for diseases such as Pendred syndrome, which arise from transport defects of misfolded proteins.

Original languageEnglish
Article number11386
JournalNature communications
Volume7
DOIs
Publication statusPublished - 2016 Apr 25

Fingerprint

secretions
proteins
cells
mutations
Proteins
Protein folding
auditory defects
Defects
Mutation
Far East
Protein Folding
defects
Audition
Hearing Loss
Proteomics
folding
Small Interfering RNA
Screening
Up-Regulation
screening

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Jung, Jinsei ; Kim, Jiyoon ; Roh, Shin Hye ; Jun, Ikhyun ; Sampson, Robert D. ; Gee, Heon Yung ; Choi, Jae Young ; Lee, Min Goo. / The HSP70 co-chaperone DNAJC14 targets misfolded pendrin for unconventional protein secretion. In: Nature communications. 2016 ; Vol. 7.
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abstract = "Mutations in SLC26A4, which encodes pendrin, are responsible for hearing loss with an enlarged vestibular aqueduct and Pendred syndrome. The most prevalent mutation in East Asia is p.H723R (His723Arg), which leads to defects in protein folding and cell-surface expression. Here we show that H723R-pendrin can be rescued to the cell surface by an HSP70 co-chaperone DNAJC14-dependent unconventional trafficking pathway. Blockade of ER-to-Golgi transport or activation of ER stress signals induced Golgi-independent cell-surface expression of H723R-pendrin and restored its cell-surface Cl - /HCO 3 - exchange activity. Proteomic and short interfering RNA screenings with subsequent molecular analyses showed that Hsc70 and DNAJC14 are required for the unconventional trafficking of H723R-pendrin. Moreover, DNAJC14 upregulation was able to induce the unconventional cell-surface expression of H723R-pendrin. These results indicate that Hsc70 and DNAJC14 play central roles in ER stress-associated unconventional protein secretion and are potential therapeutic targets for diseases such as Pendred syndrome, which arise from transport defects of misfolded proteins.",
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The HSP70 co-chaperone DNAJC14 targets misfolded pendrin for unconventional protein secretion. / Jung, Jinsei; Kim, Jiyoon; Roh, Shin Hye; Jun, Ikhyun; Sampson, Robert D.; Gee, Heon Yung; Choi, Jae Young; Lee, Min Goo.

In: Nature communications, Vol. 7, 11386, 25.04.2016.

Research output: Contribution to journalArticle

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AU - Sampson, Robert D.

AU - Gee, Heon Yung

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AU - Lee, Min Goo

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