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EMC3 regulates trafficking and pulmonary toxicity of the SFTPCI73T mutation associated with interstitial lung disease
Xiaofang Tang, … , Xinhua Lin, Jeffrey A. Whitsett
Xiaofang Tang, … , Xinhua Lin, Jeffrey A. Whitsett
Published October 15, 2024
Citation Information: J Clin Invest. 2024;134(23):e173861. https://doi.org/10.1172/JCI173861.
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Research Article Cell biology Pulmonology

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

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Abstract

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 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 therapeutical targets for SFTPCI73T-associated interstitial lung disease.

Authors

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

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Figure 4

Loss of Emc3 rescues trafficking defects and mitochondria dysfunction caused by SP-C(I73T).

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Loss of Emc3 rescues trafficking defects and mitochondria dysfunction ca...
(A) Protein sequencing data were obtained from AT2 cells sorted from control (WT/CreERT), SftpcI73T heterozygous (I73T/CreERT), and I73T/CreERT;Emc3Δ/Δ mice on P21 after treatment with tamoxifen as in Figure 2A. Protein levels in I73T/CreERT;Emc3Δ/Δ AT2 cells were compared with that in the other 2 genotypes and proteins significantly altered in 1 or more conditions were unbiasedly clustered and visualized in a z score–normalized heatmap. Group 1, proteins induced in AT2 cells from I73T/CreERT;Emc3Δ/Δ lungs; Group 2, proteins rescued by Emc3 deletion (induced in I73T/CreERT and reversed in I73T/CreERT;Emc3Δ/Δ); Group 3, proteins only repressed in I73T/CreERT;Emc3Δ/Δ AT2 cells. Functional enrichment analyses of these proteins were performed using Toppfun. A subset of significant relationships was represented by graphing the corresponding –log10 (P value). (B) Lung sections were prepared from P21 mice treated with tamoxifen as in Figure 2A and stained for proSP-C (green), an early endosome marker, EEA1 (red), and DAPI (blue). Diffuse staining of EEA1 in AT2 cells is shown in WT/CreERT controls. SP-C(I73T) accumulated with EEA1 in close proximity to plasma membranes. Emc3 deletion restored the diffuse intracellular distribution of both proSP-C(I73T) and EEA1. (C) Lung sections were prepared from P21 mice treated with tamoxifen as in Figure 2A and were stained for proSP-C (green), TOM20 (red), and DAPI (blue). Mitochondrial outer membrane protein TOM20 accumulated in SP-C(I73T)–expressing AT2 cells and was restored by deletion of Emc3. Scale bars: 20μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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