# ERP29: PROMOTING ION CHANNEL BIOGENESIS FROM THE ER LUMEN

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $394,660

## Abstract

PROJECT SUMMARY/ABSTRACT
 Cystic Fibrosis (CF) and hypertension are life-shortening diseases of epithelial ion transport. In the CF
airway, when the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is functionally absent, there is
a relative and unbalanced increase in the activity of the Epithelial Sodium Channel (ENaC) that leads to Na+
absorption from and depletion of the airway surface liquid. In turn, this impairs mucociliary clearance and
predisposes the CF airway to bacterial colonization/infection. ENaC can also play a key role in causing
hypertension; abnormally increased function of ENaC in the distal tubule of the nephron leads to increased Na+
retention, increased blood volume and hypertension. The regulation of ENaC activity is therefore key in
understanding and developing therapies for these diseases of epithelial ion transport.
 A critical determinant of ENaC's open probability (Po), and therefore its function, is the proteolytic cleavage of
the luminal/extracellular loops of its α and γ subunits; uncleaved channel has Po ~0, while fully cleaved channel
has Po ~1. In fact, increased ENaC cleavage is reported in CF airway epithelial cells. Interestingly, ENaC can be
delivered to the epithelial surface in either a cleaved or an uncleaved form, but the factor(s) that determine
whether or not ENaC undergoes cleavage during biogenesis are not known.
 We have extensively studied Sodium 4-Phenylbutyrate (4PBA), the prototype small molecule corrector of the
aberrant trafficking of the most common CF causing CFTR mutation, ΔF508. Others demonstrated that 4PBA
also increases the function of ENaC. We found that ERp29 (Endoplasmic Reticulum Protein of 29 kD), a novel,
ubiquitously expressed endoplasmic reticulum (ER) luminal chaperone has increased expression in bronchiolar
epithelial cells treated with 4PBA, and that ERp29 promotes the trafficking of both wild type and ΔF508-CFTR.
ERp29 was thus the first ER luminal component demonstrated to positively influence CFTR trafficking.
 We have also recently demonstrated that ERp29 promotes the function of ENaC. Interestingly, our data
suggest that ERp29 does this by directing ENaC for cleavage in the Golgi during biogenesis, as depletion of
ERp29 decreased ENaC function without altering expression of ENaC at the apical epithelial surface. The
hypothesis of this proposal is that interaction of the luminal face of epithelial ion channels, such as CFTR and
ENaC, with ERp29 during their biogenesis is required to direct these clients from the ER to the Golgi. This
hypothesis will be tested with studies Specifically Aiming: 1) To test if ER-luminal facing mutations of CFTR that
cause CF and are predicted to not interact with ERp29 have abnormal maturation. 2) To test the mechanism by
which ERp29 directs ENaC to the Golgi during biogenesis. 3) To test the mechanism by which ENaC can bypass
cleavage in the Golgi en route to the plasma membrane. These studies will yield key mechanistic insights th...

## Key facts

- **NIH application ID:** 10302185
- **Project number:** 7R01HL135670-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Ronald C Rubenstein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $394,660
- **Award type:** 7
- **Project period:** 2017-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10302185

## Citation

> US National Institutes of Health, RePORTER application 10302185, ERP29: PROMOTING ION CHANNEL BIOGENESIS FROM THE ER LUMEN (7R01HL135670-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10302185. Licensed CC0.

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