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

Autor:	Tang X; Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China., Wei W; Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China., Sun Y; Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China., Weaver TE; Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America., Nakayasu ES; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America., Clair G; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America., Snowball JM; Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America., Na CL; Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America., Apsley KS; Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America., Martin EP; Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America., Kotton DN; Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America., Alysandratos KD; Department of Medicine, The Pulmonary Center, Center for Regenerative Medic, Boston University School of Medicine, Boston, United States of America., Huo J; Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America., Molkentin JD; Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America., Gower WA; Division of Pediatric Pulmonology and Program for Rare and Interstitial Lun, University of North Carolina School of Medicine, Chapel Hill, United States of America., Lin X; Greater Bay Area Institute of Precision Medicine, Fudan University, Shanghai, China., Whitsett JA; Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biol, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2024 Oct 15. Date of Electronic Publication: 2024 Oct 15.
DOI:	10.1172/JCI173861
Abstrakt:	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 purification-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.
Databáze:	MEDLINE
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