# Role of EMC3/TMEM111 in Alveolar Epithelial Cell Function

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $539,416

## Abstract

PROJECT SUMMARY: Role of Emc3/Tmem111 in Alveolar Type 2 (AT2) Cell Function.
Overview: Pulmonary surfactant is a complex mixture of lipids and proteins produced by AT2 cells that is
secreted into the alveolar spaces to reduce surface tension and prevent alveolar collapse during ventilation.
Lack of pulmonary surfactant leads to respiratory failure in 1) preterm infants and adults with respiratory
distress syndrome (RDS/ARDS) and 2) chronic interstitial lung diseases (ILD) caused by mutations in genes
encoding surfactant proteins (e.g. ABCA3, SFTPA, SFTPB, and SFTPC). ABCA3, a phospholipid transporter,
and SP-B are critical for the formation of lamellar bodies and for surfactant function. Misrouting of mutant SP-
C or loss of ABCA3 cause AT2 cell injury leading to ILD. While genetic diagnoses for diseases of surfactant
homeostasis are now possible in newborn infants, there are no effective therapies other than lung
transplantation for these usually fatal disorders. Lacking is knowledge regarding the specific AT2 cell
machinery that integrates the routing and processing of surfactant lipids and proteins in the AT2 cells, and the
molecular mechanisms by which disruption of these pathways causes AT2 cell injury, surfactant deficiency and
alveolar remodeling. We have identified Emc3/Tmem111 as a critical ER component of the cellular
machinery that regulates the processing, routing, and function of SP-B, SP-C, ABCA3, and lipids in
AT2 cells. In this project, we will identify the intracellular sites and functions of EMC3 in vivo and in vitro. The
effects of loss of function of EMC3 on lung structure, surfactant homeostasis, and lung function will be
determined. Its role in a proposed cell-specific ER/EMC3 complex, its protein cargoes, and its requirement for
surfactant homeostasis in AT2 cell function will be identified in mouse models in vivo, in primary AT2 cells
isolated from the mice, and immortalized airway epithelial cells, representing models of both human and
mouse AT2 cell function. Immunofluorescence and confocal microscopy will be used to precisely identify the
intracellular sites of action, and an Emc3-flag-tomato construct will be used in conjunction with antibodies for
Co-IP experiments to identify protein cargoes by proteomic analysis. Lipidomic analyses and ultrastructural
studies will identify its role in lamellar body formation and surfactant lipid homeostasis. The role of EMC3 in
ER stress and the recognition, stabilization, and chaperoning of mutant surfactant proteins and ABCA3
produced by defects in SFTPC and ABCA3 genes will be identified. We will determine whether EMC3/EMC
complex is regulated by and influences ER stress and endoplasmic reticulum associated degradation (ERAD)
pathways that causes AT2 cell toxicity.

## Key facts

- **NIH application ID:** 9918951
- **Project number:** 5R01HL136722-04
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** XINHUA LIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $539,416
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918951

## Citation

> US National Institutes of Health, RePORTER application 9918951, Role of EMC3/TMEM111 in Alveolar Epithelial Cell Function (5R01HL136722-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9918951. Licensed CC0.

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