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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 
 NATURE COMMUNICATIONS, Vol.7 : 11386, 2016 
Journal Title
Issue Date
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.
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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Ji Yoon(김지윤)
Noh, Shin Hye(노신혜)
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Jun, Ik Hyun(전익현) ORCID logo https://orcid.org/0000-0002-2160-1679
Jung, Jinsei(정진세) ORCID logo https://orcid.org/0000-0003-1906-6969
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
Choi, Jae Young(최재영) ORCID logo https://orcid.org/0000-0001-9493-3458
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