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EMC3 regulates trafficking and pulmonary toxicity of the SFTPCI73T mutation associated with interstitial lung disease

Journal Article · · Journal of Clinical Investigation
DOI:https://doi.org/10.1172/jci173861· OSTI ID:2483343
 [1];  [2];  [2];  [3];  [4];  [4];  [3];  [3];  [3];  [3];  [5];  [5];  [3];  [3];  [6];  [2];  [3]
  1. Fudan Univ., Shanghai (China); Cincinnati Children's Hospital Medical Center, OH (United State)
  2. Fudan Univ., Shanghai (China)
  3. Cincinnati Children's Hospital Medical Center, OH (United State)
  4. Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
  5. Boston Univ., MA (United States)
  6. Univ. of North Carolina, Chapel Hill, NC (United States)
+ Show Author Affiliations
The most common mutation in surfactant protein C gene (SFTPC), SFTPCI73T, causes interstitial lung disease with few therapeutic options. We previously demonstrated that EMC3, an important component of the multiprotein endoplasmic reticulum membrane complex (EMC), is required for surfactant homeostasis in alveolar type 2 epithelial (AT2) cells at birth. In the present study, we investigated the role of EMC3 in the control of SFTPCI73T metabolism and its associated alveolar dysfunction. Using a knock-in mouse model phenocopying the I73T mutation, we demonstrated that conditional deletion of Emc3 in AT2 cells rescued alveolar remodeling/simplification defects in neonatal and adult mice. Proteomic analysis revealed that Emc3 depletion reversed the disruption of vesicle trafficking pathways and rescued the mitochondrial dysfunction associated with I73T mutation. Affinity mass spectrometry analysis identified potential EMC3 interacting proteins in lung AT2 cells, including Valosin Containing Protein (VCP) and its interactors. Treatment of SftpcI73T knock-in mice and SFTPCI73T expressing iAT2 cells derived from SFTPCI73T patient-specific iPSCs with the specific VCP inhibitor CB5083 restored alveolar structure and SFTPCI73T trafficking respectively. Taken together, the present work identifies the EMC complex and VCP in the metabolism of the disease-associated SFTPCI73T mutant, providing novel therapeutical targets for SFTPCI73T-associated interstitial lung disease.
Research Organization:
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC05-76RL01830
OSTI ID:
2483343
Report Number(s):
PNNL-SA--184548
Journal Information:
Journal of Clinical Investigation, Journal Name: Journal of Clinical Investigation Journal Issue: 23 Vol. 134; ISSN 1558-8238
Publisher:
American Society for Clinical InvestigationCopyright Statement
Country of Publication:
United States
Language:
English

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