IRE1α kinase-mediated unconventional protein secretion rescues misfolded CFTR and pendrin.

The most prevalent pathogenic mutations in the CFTR (Delta F508) and SLC26A4/pendrin (p.H723R), which cause cystic fibrosis and congenital hearing loss, respectively, evoke protein misfolding and subsequent defects in their cell surface trafficking. Here, we report that activation of the IRE1 alpha kinase pathway can rescue the cell surface expression of Delta F508-CFTR and p.H723R-pendrin through a Golgi-independent unconventional protein secretion (UPS) route. In mammalian cells, inhibition of IRE1 alpha kinase, but not inhibition of IRE1 alpha endonuclease and the downstream effector XBP1, inhibited CFTR UPS. Treatment with the IRE1 alpha kinase activator, (E)-2-(2-chlorostyryl)-3,5,6-trimethyl-pyrazine (CSTMP), rescued cell surface expression and functional activity of Delta F508-CFTR and p. H723R-pendrin. Treatment with a nontoxic dose of CSTMP to Delta F508-CFTR mice restored CFTR surface expression and CFTR-mediated anion transport in the mouse colon. These findings suggest that UPS activation via IRE1 alpha kinase is a strategy to treat diseases caused by defective cell surface trafficking of membrane proteins, including Delta F508-CFTR and p.H723R-pendrin.