EMC3 regulates trafficking and pulmonary toxicity of the <i>SFTPC<sup>I73T</sup></i> mutation associated with interstitial lung disease

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

doi:10.1172/JCI173861

¹Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China

²Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

³Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America

⁴Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America

⁵Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

⁶Division of Pediatric Pulmonology and Program for Rare and Interstitial Lun, University of North Carolina School of Medicine, Chapel Hill, United States of America

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¹Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China

²Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

³Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America

⁴Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America

⁵Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

⁶Division of Pediatric Pulmonology and Program for Rare and Interstitial Lun, University of North Carolina School of Medicine, Chapel Hill, United States of America

Find articles by Wei, W. in: JCI | PubMed | Google Scholar

¹Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China

²Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

³Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America

⁴Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America

⁵Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

⁶Division of Pediatric Pulmonology and Program for Rare and Interstitial Lun, University of North Carolina School of Medicine, Chapel Hill, United States of America

Find articles by Sun, Y. in: JCI | PubMed | Google Scholar

¹Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China

²Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

³Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America

⁴Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America

⁵Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

⁶Division of Pediatric Pulmonology and Program for Rare and Interstitial Lun, University of North Carolina School of Medicine, Chapel Hill, United States of America

Find articles by Weaver, T. in: JCI | PubMed | Google Scholar

¹Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China

²Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

³Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America

⁴Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America

⁵Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

⁶Division of Pediatric Pulmonology and Program for Rare and Interstitial Lun, University of North Carolina School of Medicine, Chapel Hill, United States of America

Find articles by Nakayasu, E. in: JCI | PubMed | Google Scholar |

¹Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China

²Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

³Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America

⁴Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America

⁵Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

⁶Division of Pediatric Pulmonology and Program for Rare and Interstitial Lun, University of North Carolina School of Medicine, Chapel Hill, United States of America

Find articles by Clair, G. in: JCI | PubMed | Google Scholar |

¹Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China

²Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

³Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America

⁴Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America

⁵Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

⁶Division of Pediatric Pulmonology and Program for Rare and Interstitial Lun, University of North Carolina School of Medicine, Chapel Hill, United States of America

Find articles by Snowball, J. in: JCI | PubMed | Google Scholar

¹Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China

²Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

³Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America

⁴Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America

⁵Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

⁶Division of Pediatric Pulmonology and Program for Rare and Interstitial Lun, University of North Carolina School of Medicine, Chapel Hill, United States of America

Find articles by Na, C. in: JCI | PubMed | Google Scholar |

¹Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China

²Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

³Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America

⁴Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America

⁵Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

⁶Division of Pediatric Pulmonology and Program for Rare and Interstitial Lun, University of North Carolina School of Medicine, Chapel Hill, United States of America

Find articles by Apsley, K. in: JCI | PubMed | Google Scholar

¹Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China

²Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

³Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America

⁴Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America

⁵Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

⁶Division of Pediatric Pulmonology and Program for Rare and Interstitial Lun, University of North Carolina School of Medicine, Chapel Hill, United States of America

Find articles by Martin, E. in: JCI | PubMed | Google Scholar

¹Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China

²Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

³Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America

⁴Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America

⁵Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

⁶Division of Pediatric Pulmonology and Program for Rare and Interstitial Lun, University of North Carolina School of Medicine, Chapel Hill, United States of America

Find articles by Kotton, D. in: JCI | PubMed | Google Scholar |

¹Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China

²Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

³Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America

⁴Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America

⁵Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

⁶Division of Pediatric Pulmonology and Program for Rare and Interstitial Lun, University of North Carolina School of Medicine, Chapel Hill, United States of America

Find articles by Alysandratos, K. in: JCI | PubMed | Google Scholar |

¹Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China

²Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

³Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America

⁴Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America

⁵Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

⁶Division of Pediatric Pulmonology and Program for Rare and Interstitial Lun, University of North Carolina School of Medicine, Chapel Hill, United States of America

Find articles by Huo, J. in: JCI | PubMed | Google Scholar

¹Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China

²Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

³Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America

⁴Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America

⁵Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

⁶Division of Pediatric Pulmonology and Program for Rare and Interstitial Lun, University of North Carolina School of Medicine, Chapel Hill, United States of America

Find articles by Molkentin, J. in: JCI | PubMed | Google Scholar |

¹Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China

²Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

³Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America

⁴Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America

⁵Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

⁶Division of Pediatric Pulmonology and Program for Rare and Interstitial Lun, University of North Carolina School of Medicine, Chapel Hill, United States of America

Find articles by Gower, W. in: JCI | PubMed | Google Scholar

¹Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China

²Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

³Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America

⁴Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America

⁵Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

⁶Division of Pediatric Pulmonology and Program for Rare and Interstitial Lun, University of North Carolina School of Medicine, Chapel Hill, United States of America

Find articles by Lin, X. in: JCI | PubMed | Google Scholar

¹Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China

²Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

³Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America

⁴Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America

⁵Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

⁶Division of Pediatric Pulmonology and Program for Rare and Interstitial Lun, University of North Carolina School of Medicine, Chapel Hill, United States of America

Find articles by Whitsett, J. in: JCI | PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI173861.
Copyright © 2024, Tang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published October 15, 2024 - Version history

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 purification-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.

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

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