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

Tang, Xiaofang; Wei, Wei; Sun, Yuqing; Weaver, Timothy E.; Nakayasu, Ernesto S.; Clair, Geremy; Snowball, John M.; Na, Cheng-Lun; Apsley, Karen S.; Martin, Emily P.; Kotton, Darrell N.; Alysandratos, Konstantinos-Dionysios; Huo, Jiuzhou; Molkentin, Jeffery D.; Gower, William A.; Lin, Xinhua; Whitsett, Jeffrey A.

doi:10.1172/jci173861

EMC3 regulates trafficking and pulmonary toxicity of the SFTPC^I73T mutation associated with interstitial lung disease

Journal Article · Tue Oct 15 00:00:00 EDT 2024 · Journal of Clinical Investigation

DOI:https://doi.org/10.1172/jci173861· OSTI ID:2483343

Tang, Xiaofang ^[1]; Wei, Wei ^[2]; Sun, Yuqing ^[2]; Weaver, Timothy E. ^[3]; ^[4]; ^[4]; Snowball, John M. ^[3]; ^[3]; Apsley, Karen S. ^[3]; Martin, Emily P. ^[3]; ^[5]; ^[5]; Huo, Jiuzhou ^[3]; ^[3]; Gower, William A. ^[6]; Lin, Xinhua ^[2]; Whitsett, Jeffrey A. ^[3]

Fudan Univ., Shanghai (China); Cincinnati Children's Hospital Medical Center, OH (United State)
Fudan Univ., Shanghai (China)
Cincinnati Children's Hospital Medical Center, OH (United State)
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Boston Univ., MA (United States)
Univ. of North Carolina, Chapel Hill, NC (United States)

The most common mutation in surfactant protein C gene (SFTPC), SFTPC^I73T, 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 SFTPC^I73T 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 Sftpc^I73T knock-in mice and SFTPC^I73T expressing iAT2 cells derived from SFTPC^I73T patient-specific iPSCs with the specific VCP inhibitor CB5083 restored alveolar structure and SFTPC^I73T trafficking respectively. Taken together, the present work identifies the EMC complex and VCP in the metabolism of the disease-associated SFTPC^I73T mutant, providing novel therapeutical targets for SFTPC^I73T-associated interstitial lung disease.

View Accepted Manuscript (DOE)

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, Vol. 134, Issue 23; ISSN 1558-8238

Publisher:: American Society for Clinical InvestigationCopyright Statement

Country of Publication:: United States

Language:: English

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