RT Journal Article
SR Electronic
T1 DNAJB12 and Hsp70 Facilitate the Conformation Specific Degradation of Arrested N1303K-CFTR Intermediates by ERQC-Autophagy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.28.358580
DO 10.1101/2020.10.28.358580
A1 Lihua He
A1 Andrew S. Kennedy
A1 Scott Houck
A1 Andrei Aleksandrov
A1 Nancy L. Quinney
A1 Deborah M. Cholon
A1 Martina Gentzsch
A1 Scott H. Randell
A1 Hong Yu Ren
A1 Douglas M. Cyr
YR 2020
UL http://biorxiv.org/content/early/2020/10/28/2020.10.28.358580.abstract
AB Proteotoxic stress, intrinsic folding inefficiencies, and disease-related mutations challenge cellular quality control systems tasked with proteome biogenesis and suppressing proteotoxicity. The ER-transmembrane Hsp40 DNAJB12 and Hsp70 cooperate in protein maintenance by triaging nascent membrane proteins for folding versus degradation. N1303K is the second most common CF causing mutation in CFTR, but unlike F508del-CFTR, its biogenic and functional defects are resistant to correction by VX-809. VX-809 stimulates the accumulation of kinetically trapped N1303K-CFTR intermediates that exhibit conformational features of folded CFTR but remain associated with DNAJB12-Hsp70. Stable N1303K-CFTR intermediates are resistant to ERAD and become concentrated in ER-tubules associated with autophagy initiation sites containing WIPI1, FIP200, and LC3. Budding of autophagosomes containing N1303K-CFTR from omegasomes occurs where autolysosomes dock to WIPI1 rings.Mechanisms will be discussed for Hsp40 and Hsp70 action in the sorting of N1303K-CFTR intermediates for secretion versus degradation by ERAD or ERQC-autophagy.Competing Interest StatementThe authors have declared no competing interest.