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ERP29 INFLUENCES CFTR MATURATION THROUGH A LUMINAL Y‐X‐F MOTIF
Author(s) -
Suaud Laurence,
Podrat Jerica,
Rubenstein Ronald
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.844.12
Subject(s) - endoplasmic reticulum , mutant , microbiology and biotechnology , cystic fibrosis transmembrane conductance regulator , biogenesis , copii , chaperone (clinical) , golgi apparatus , cystic fibrosis , intracellular , phenylbutyrate , chemistry , unfolded protein response , secretory pathway , biology , genetics , biochemistry , endocrinology , gene , medicine , pathology
Sodium 4‐Phenylbutyrate (4PBA) corrects the intracellular trafficking of F508del‐CFTR in Cystic Fibrosis (CF) epithelial cells. 4PBA is known to modulate the expression of a number of molecular chaperones. We previously demonstrated that a novel endoplasmic reticulum (ER) chaperone , ERp29, had ~50% increased expression in IB3‐1 CF bronchiolar epithelial cells in response to 4PBA. Our data from overexpression and siRNA‐mediated depletion experiments are consistent with ERp29 playing a critical role in the biogenesis of CFTR and contributing to improved intracellular trafficking of F508del‐CFTR. The mechanism by which Erp29 acts is not known, but our data suggest that ERp29 is critical for CFTR to interact with Coat Complex II (COP II) ER exit machinery. ERp29 is suggested to interact with either ‐(F,Y)‐(F,Y)‐ or ‐(F,Y)‐X‐(F,Y)‐ motifs on clients. CFTR has only one luminal motif consistent with this pattern ( 1014 Y‐I‐F 1016 ), and two rare mutations in this motif that appear to cause CF, Y1014C and F1016C. We expressed these mutant in CFBE41o‐ CF epithelial cells, and found that mature, Golgi‐processed CFTR was not present; only immature CFTR was found on immunoblots. These data suggest that Y1014C‐ and F1016C‐CFTR have impaired trafficking as their underlying mechanism of causing CF. Future studies will test if these mutants interact with ERp29 , and if these mutants lack interaction with the Sec24D cargo recognition component of COP II even though they retain the diacidic motif in NBD1 that is crucial for CFTR's interaction with Sec24D/COP II. These data will help us understand the mechanism by which ERp29 promotes CFTR biogenesis.