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Novel insights into surfactant protein C trafficking revealed through the study of a pathogenic mutant

Jennifer A. Dickens, Eimear N. Rutherford, Susana Abreu, Joseph E. Chambers, Matthew O. Ellis, Annemarie van Schadewijk, Pieter S. Hiemstra, Stefan J. Marciniak
European Respiratory Journal 2021; DOI: 10.1183/13993003.00267-2021
Jennifer A. Dickens
1Cambridge Institute for Medical Research, Cambridge, UK
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  • For correspondence: jac72@cam.ac.uk
Eimear N. Rutherford
1Cambridge Institute for Medical Research, Cambridge, UK
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Susana Abreu
1Cambridge Institute for Medical Research, Cambridge, UK
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Joseph E. Chambers
1Cambridge Institute for Medical Research, Cambridge, UK
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Matthew O. Ellis
1Cambridge Institute for Medical Research, Cambridge, UK
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Annemarie van Schadewijk
2Department of Pulmonology, Leiden University Medical Center, Leiden, Netherlands
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Pieter S. Hiemstra
2Department of Pulmonology, Leiden University Medical Center, Leiden, Netherlands
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  • ORCID record for Pieter S. Hiemstra
Stefan J. Marciniak
1Cambridge Institute for Medical Research, Cambridge, UK
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Abstract

Alveolar epithelial cell dysfunction plays an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) but remains incompletely understood. Some monogenic forms of pulmonary fibrosis are associated with expression of mutant surfactant protein C (SFTPC). The commonest pathogenic mutant, I73T, mislocalises to the alveolar epithelial cell plasma membrane and displays a toxic-gain-of-function. Because the mechanisms explaining the link between this mutant and IPF are incompletely understood, we sought to interrogate SFTPC trafficking in health and disease to understand the functional significance of SFTPC-I73T relocalisation.

We performed mechanistic analysis of SFTPC trafficking in a cell model that reproduces the in vivo phenotype and validated findings in human primary alveolar organoids.

We show that wild-type SFTPC takes an unexpected indirect trafficking route via the plasma membrane and undergoes the first of multiple cleavage events before reaching the multivesicular body (MVB) for further processing. SFTPC-I73T takes this same route, but its progress is retarded both at the cell surface and due to failure of trafficking into the MVB. Unable to undergo onward trafficking, it is recycled to the plasma membrane as a partially cleaved intermediate.

These data show for the first time that all SFTPC transits the cell surface during normal trafficking, and the I73T mutation accumulates at the cell surface through both retarded trafficking and active recycling. This understanding of normal SFTPC trafficking and how the I73T mutant disturbs it provides novel insight into SFTPC biology in health and disease, and in the contribution of the SFTPC mutant to IPF development.

Footnotes

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: Dr. Dickens has nothing to disclose.

Conflict of interest: Ms. Rutherford has nothing to disclose.

Conflict of interest: Dr. Abreu has nothing to disclose.

Conflict of interest: Dr. Chambers has nothing to disclose.

Conflict of interest: Mr. Ellis has nothing to disclose.

Conflict of interest: Dr. van Schadewijk has nothing to disclose.

Conflict of interest: Dr. Hiemstra has nothing to disclose.

Conflict of interest: Prof. Marciniak has nothing to disclose.

This is a PDF-only article. Please click on the PDF link above to read it.

  • Received January 28, 2021.
  • Accepted May 16, 2021.
  • Copyright ©The authors 2021
http://creativecommons.org/licenses/by/4.0/

This version is distributed under the terms of the Creative Commons Attribution Licence 4.0.

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Novel insights into surfactant protein C trafficking revealed through the study of a pathogenic mutant
Jennifer A. Dickens, Eimear N. Rutherford, Susana Abreu, Joseph E. Chambers, Matthew O. Ellis, Annemarie van Schadewijk, Pieter S. Hiemstra, Stefan J. Marciniak
European Respiratory Journal Jan 2021, 2100267; DOI: 10.1183/13993003.00267-2021

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Novel insights into surfactant protein C trafficking revealed through the study of a pathogenic mutant
Jennifer A. Dickens, Eimear N. Rutherford, Susana Abreu, Joseph E. Chambers, Matthew O. Ellis, Annemarie van Schadewijk, Pieter S. Hiemstra, Stefan J. Marciniak
European Respiratory Journal Jan 2021, 2100267; DOI: 10.1183/13993003.00267-2021
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