Thiol isomerase ERp57 targets and modulates the lectin pathway of complement activation

Thiol isomerase ERp57 targets and modulates the lectin pathway of complement activation.

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Item Type: Article
Status: Published
Official URL:
Journal or Publication Title: Journal of Biological Chemistry
Volume: 294
Number: 13
Page Range: pp. 4878-4888
Date: 2019
Divisions: ACRF Centenary Cancer Research Centre
Depositing User: General Admin
Identification Number: 10.1074/jbc.RA118.006792
ISSN: 0021-9258
Date Deposited: 21 Dec 2020 05:58

ER protein 57 (ERp57), a thiol isomerase secreted from vascular cells, is essential for complete thrombus formation in vivo, but other extracellular ERp57 functions remain unexplored. Here, we employed a kinetic substrate-trapping approach to identify extracellular protein substrates of ERp57 in platelet-rich plasma. MS-based identification with immunochemical confirmation combined with gene ontology enrichment analysis revealed that ERp57 targets, among other substrates, components of the lectin pathway of complement activation: mannose-binding lectin, ficolin-2, ficolin-3, collectin-10, collectin-11, mannose-binding lectin-associated serine protease-1, and mannose-binding lectin-associated serine protease-2. Ficolin-3, the most abundant lectin pathway initiator in humans, circulates as disulfide-linked multimers of a monomer. ERp57 attenuated ficolin-3 ligand recognition and complement activation by cleaving intermolecular disulfide bonds in large ficolin-3 multimers, thereby reducing multimer size and ligand-binding affinity. We used MS to identify the disulfide-bonding pattern in ficolin-3 multimers and the disulfide bonds targeted by ERp57 and found that Cys6 and Cys23 in the N-terminal region of ficolin-3 form the intermolecular disulfide bonds in ficolin-3 multimers that are reduced by ERp57. Our results not only demonstrate that ERp57 can negatively regulate complement activation, but also identify a control mechanism for lectin pathway initiation in the vasculature. We conclude that extensive multimerization in large ficolin-3 multimers leads to a high affinity for ligands and strong complement-activating potential and that ERp57 suppresses complement activation by cleaving disulfide bonds in ficolin-3 and reducing its multimer size.

Keywords: ER protein 57 (ERp57); complement system; disulfide; ficolin; innate immunity; lectin pathway; mass spectrometry (MS); redox regulation; thiol isomerase.

© 2019 Eriksson et al.

Eriksson, Oskar
Chiu, Joyce
Hogg, Philip J.
Atkinson, John P.
Liszewski, M. Kathryn
Flaumenhaft, Robert
Furie, Bruce
Last Modified: 21 Dec 2020 05:58

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