Soluble collectin-12 mediates C3-independent docking of properdin that activates the alternative pathway of complement

  1. Jie Zhang
  2. Lihong Song
  3. Dennis V Pedersen
  4. Anna Li
  5. John D Lambris
  6. Gregers Rom Andersen
  7. Tom Eirik Mollnes
  8. Ying Jie Ma  Is a corresponding author
  9. Peter Garred  Is a corresponding author
  1. Rigshospitalet/Copenhagen University, Denmark
  2. Aarhus University, Denmark
  3. University of Pennsylvania, United States
  4. University of Oslo, Norway

Abstract

Properdin stabilizes the alternative C3 convertase (C3bBb), whereas its role as pattern recognition molecule mediating complement activation is disputed for decades. Previously, we have found that soluble collectin-12 (sCL-12) synergizes complement alternative pathway (AP) activation. However, whether this observation is C3 dependent is unknown. By application of the C3-inhibitor Cp40, we found that properdin in normal human serum bound to Aspergillus fumigatus solely in a C3b-dependent manner. Cp40 also prevented properdin binding when properdin-depleted serum reconstituted with purified properdin was applied, in analogy with the findings achieved by C3-depleted serum. However, when opsonized with sCL-12, properdin bound in a C3-independent manner exclusively via its tetrameric structure and directed in situ C3bBb assembly. In conclusion, a prerequisite for properdin binding and in situ C3bBb assembly was the initial docking of sCL-12. This implies a new important function of properdin in host defence bridging pattern recognition and specific AP activation.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Jie Zhang

    Department of Clinical Immunology, Rigshospitalet/Copenhagen University, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4472-3468
  2. Lihong Song

    Department of Clinical Immunology, Rigshospitalet/Copenhagen University, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
  3. Dennis V Pedersen

    Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
    Competing interests
    No competing interests declared.
  4. Anna Li

    Department of Clinical Immunology, Rigshospitalet/Copenhagen University, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
  5. John D Lambris

    Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    John D Lambris, inventor of patents (Patent Number: 9630992) and/or patent applications 426 (Application Number: 15/126,937) that describe the use of complement inhibitors for therapeutic purposes, the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors (i.e., third-generation compstatins) for clinical applications, and the inventor of the compstatin technology licensed to Apellis Pharmaceuticals (i.e., 4[1MeW]7W/POT-4/APL-1 and PEGylated derivatives)..
  6. Gregers Rom Andersen

    Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6292-3319
  7. Tom Eirik Mollnes

    Department of Immunology, University of Oslo, Oslo, Norway
    Competing interests
    No competing interests declared.
  8. Ying Jie Ma

    Department of Clinical Immunology, Rigshospitalet/Copenhagen University, Copenhagen, Denmark
    For correspondence
    mayingjie606@hotmail.com
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4003-2579
  9. Peter Garred

    Department of Clinical Immunology, Rigshospitalet/Copenhagen University, Copenhagen, Denmark
    For correspondence
    peter.garred@regionh.dk
    Competing interests
    No competing interests declared.

Funding

Kirsten og Freddy Johansens Fond (Research fund)

  • Ying Jie Ma

Novo Nordisk (Research fund)

  • Peter Garred

Købmand I Odense Johan og Hanne Weimann Født Seedorffs Legat (Research fund)

  • Ying Jie Ma

Alfred Benzon Foundation (Research fund)

  • Ying Jie Ma
  • Peter Garred

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Frank L van de Veerdonk, Radboud University Medical Center, Netherlands

Version history

  1. Received: July 9, 2020
  2. Accepted: September 9, 2020
  3. Accepted Manuscript published: September 10, 2020 (version 1)
  4. Accepted Manuscript updated: September 14, 2020 (version 2)
  5. Version of Record published: September 23, 2020 (version 3)

Copyright

© 2020, Zhang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Jie Zhang
  2. Lihong Song
  3. Dennis V Pedersen
  4. Anna Li
  5. John D Lambris
  6. Gregers Rom Andersen
  7. Tom Eirik Mollnes
  8. Ying Jie Ma
  9. Peter Garred
(2020)
Soluble collectin-12 mediates C3-independent docking of properdin that activates the alternative pathway of complement
eLife 9:e60908.
https://doi.org/10.7554/eLife.60908

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