Molecular mechanism of the unconventional surface trafficking of SLC26A4 folding mutants

Abstract

Mutations in the SLC26A4 gene, which encodes pendrin, is responsible for hearing loss with an enlarged vestibular aqueduct (EVA). The most common hereditary hearing loss-related mutation in East Asia is p.H723R, which leads to defects in protein folding and cell surface expression. Here, we show that p.H723R-pendrin can be rescued via an Hsc70-dependent unconventional trafficking pathway. Golgi-independent protein trafficking enhances the surface expression of p.H723R-pendrin and successfully restores Cl-/HCO3- anion exchange activity. Hsc70 is indispensible but not sufficient by itself for successful unconventional trafficking of p.H723R-pendrin. Small interfering RNA (siRNA) screens of Hsc70 co-chaperones reveal that it is critical for DNAJC14/Drip78 to interplay with Hsc70 to allow misfolded pendrin to escape from ER associated degradation (ERAD). DNAJC14/Drip78 can be a partially sufficient factor to induce unconventional trafficking of p.H723-pendrin to the plasma membrane. These results indicate that Hsc70 and its co-chaperones have pivotal roles in unconventional protein trafficking and should be promising therapeutic targets for the treatment of misfolded protein related diseases such as Pendred syndrome and cystic fibrosis.