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Poncin MA, Van Meerbeeck P, Simpson JD, et al. Role of the Redox State of Human Peroxiredoxin-5 on Its TLR4-Activating DAMP Function. Antioxidants (Basel). 2021;10(12)doi: 10.3390/antiox10121902.
Poncin, M. A., Van Meerbeeck, P., Simpson, J. D., Clippe, A., Tyckaert, F., Bouillenne, F., Degand, H., Matagne, A., Morsomme, P., Knoops, B., & Alsteens, D. (2021). Role of the Redox State of Human Peroxiredoxin-5 on Its TLR4-Activating DAMP Function. Antioxidants (Basel, Switzerland), 10(12), . https://doi.org/10.3390/antiox10121902
Poncin, Mégane A, et al. "Role of the Redox State of Human Peroxiredoxin-5 on Its TLR4-Activating DAMP Function." Antioxidants (Basel, Switzerland) vol. 10,12 (2021). doi: https://doi.org/10.3390/antiox10121902
Poncin MA, Van Meerbeeck P, Simpson JD, Clippe A, Tyckaert F, Bouillenne F, Degand H, Matagne A, Morsomme P, Knoops B, Alsteens D. Role of the Redox State of Human Peroxiredoxin-5 on Its TLR4-Activating DAMP Function. Antioxidants (Basel). 2021 Nov 27;10(12). doi: 10.3390/antiox10121902. PMID: 34943005.
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Antioxidants (Basel). 2021 Nov 27;10(12). doi: 10.3390/antiox10121902.

Role of the Redox State of Human Peroxiredoxin-5 on Its TLR4-Activating DAMP Function.

Antioxidants (Basel, Switzerland)

Mégane A Poncin, Pierre Van Meerbeeck, Joshua D Simpson, André Clippe, François Tyckaert, Fabrice Bouillenne, Hervé Degand, André Matagne, Pierre Morsomme, Bernard Knoops, David Alsteens

Affiliations

  1. Louvain Institue of Biomolecular Science and Technology, Université catholique de Louvain, 1348 Louvain-la-Neuve, Belgium.
  2. Centre for Protein Engineering, InBioS, University of Liëge, Building B6C, Quartier Agora, Allée du 6 Août, 13, 4000 Liëge (Sart-Tilman), Belgium.

PMID: 34943005 DOI: 10.3390/antiox10121902

Abstract

Human peroxiredoxin-5 (PRDX5) is a unique redox-sensitive protein that plays a dual role in brain ischemia-reperfusion injury. While intracellular PRDX5 has been reported to act as a neuroprotective antioxidative enzyme by scavenging peroxides, once released extracellularly from necrotic brain cells, the protein aggravates neural cell death by inducing expression of proinflammatory cytokines in macrophages through activation of Toll-like receptor (TLR) 2 (TLR2) and 4 (TLR4). Although recent evidence showed that PRDX5 was able to interact directly with TLR4, little is known regarding the role of the cysteine redox state of PRDX5 on its DAMP function. To gain insights into the role of PRDX5 redox-active cysteine residues in the TLR4-dependent proinflammatory activity of the protein, we used a recombinant human PRDX5 in the disulfide (oxidized) form and a mutant version lacking the peroxidatic cysteine, as well as chemically reduced and hyperoxidized PRDX5 proteins. We first analyzed the oxidation state and oligomerization profile by Western blot, mass spectrometry, and SEC-MALS. Using ELISA, we demonstrate that the disulfide bridge between the enzymatic cysteines is required to allow improved TLR4-dependent IL-8 secretion. Moreover, single-molecule force spectroscopy experiments revealed that TLR4 alone is not sufficient to discriminate the different PRDX5 redox forms. Finally, flow cytometry binding assays show that disulfide PRDX5 has a higher propensity to bind to the surface of living TLR4-expressing cells than the mutant protein. Taken together, these results demonstrate the importance of the redox state of PRDX5 cysteine residues on TLR4-induced inflammation.

Keywords: DAMP; PRDX5; SMFS; TLR4; Toll-like receptor; atomic force microscopy; cysteine residue; peroxiredoxins; redox

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