Abstract
The luminal endoplasmic reticulum (ER) protein of 29 kDa (ERp29) is a ubiquitously expressed cellular agent with multiple critical roles. ERp29 regulates the biosynthesis and trafficking of several transmembrane and secretory proteins, including the cystic fibrosis transmembrane conductance regulator (CFTR), the epithelial sodium channel (ENaC), thyroglobulin, connexin 43 hemichannels, and proinsulin. ERp29 is hypothesized to promote ER to cis-Golgi cargo protein transport via COP II machinery through its interactions with the KDEL receptor; this interaction may facilitate the loading of ERp29 clients into COP II vesicles. ERp29 also plays a role in ER stress (ERS) and the unfolded protein response (UPR) and is implicated in oncogenesis. Here, we review the vast array of ERp29’s clients, its role as an ER to Golgi escort protein, and further suggest ERp29 as a potential target for therapies related to diseases of protein misfolding and mistrafficking.
Highlights
The endoplasmic reticulum (ER) is a membrane bound organelle present in eukaryotic cells
Because ERp29 is a member of the Protein disulfide isomerase (PDI)/thioredoxin family, but has no thioredoxin activity, it is hypothesized to function as an escort that facilitates client export from the ER
While there is still much to learn regarding ERp29’s mechanisms of action, recent data suggest that ERp29 promote the inclusion of client proteins in Complex II (COP II) vesicles for ER→Golgi transport
Summary
The endoplasmic reticulum (ER) is a membrane bound organelle present in eukaryotic cells. Further studies by our group demonstrated that ERp29 is required for proper biogenesis of wild type CFTR, and that overexpression of ERp29 can rescue the aberrant biosynthesis and trafficking of F508del CFTR (Suaud et al, 2011a) These data identify ERp29 as a novel drug target in a disease of aberrant protein folding and trafficking. ERp29 is a member of the ER luminal protein disulfide isomerase (PDI) chaperone family and contains four distinct domains (Ferrari et al, 1998) These include the N-terminal ER localization domain/signal sequence that is cleaved upon entry into the ER, the b-type PDI domain, the D-domain, and an ER retrieval KEEL (Lys-Glu-Glu-Leu) domain at the C-terminus.
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