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 and Min Goo Lee ()
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Jinsei Jung: Yonsei University College of Medicine
Jiyoon Kim: Yonsei University College of Medicine
Shin Hye Roh: Yonsei University College of Medicine
Ikhyun Jun: Yonsei University College of Medicine
Robert D. Sampson: Yonsei University College of Medicine
Heon Yung Gee: Yonsei University College of Medicine
Jae Young Choi: Yonsei University College of Medicine
Min Goo Lee: Yonsei University College of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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−/HCO3− 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.

Date: 2016
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DOI: 10.1038/ncomms11386

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