The HSP70 co-chaperone DNAJC14 targets misfolded pendrin for unconventional protein secretion.
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.
Department of Pharmacology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.|Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Jinsei
J
Jung
Department of Pharmacology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Jiyoon
J
Kim
Department of Pharmacology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Shin Hye
SH
Roh
Department of Pharmacology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Ikhyun
I
Jun
Department of Pharmacology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Robert D
RD
Sampson
Department of Pharmacology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.|Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Heon Yung
HY
Gee
Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Jae Young
JY
Choi
Department of Pharmacology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Min Goo
MG
Lee
D005326:Fetal Proteins / Q000235:genetics / Q000378:metabolism*; D006044:Goiter, Nodular / Q000235:genetics / Q000378:metabolism*; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006319:Hearing Loss, Sensorineural / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D017510:Protein Folding; D021381:Protein Transport; D000076988:Sulfate Transporters
C476535:DNAJC14 protein, human; D005326:Fetal Proteins; D018840:HSP70 Heat-Shock Proteins; D026901:Membrane Transport Proteins; D018832:Molecular Chaperones; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters