Peroxidasin-mediated bromine enrichment of basement membranes

Proc Natl Acad Sci U S A. 2020 Jul 7;117(27):15827-15836. doi: 10.1073/pnas.2007749117.

Cuiwen He ¹, Wenxin Song ¹, Thomas A Weston ¹, Caitlyn Tran ¹, Ira Kurtz ¹, Jonathan E Zuckerman ², Paul Guagliardo ³, Jeffrey H Miner ⁴, Sergey V Ivanov ⁵ ⁶, Jeremy Bougoure ³, Billy G Hudson ⁵ ⁶ ⁷ ⁸, Selene Colon ⁵ ⁶ ⁸ ⁹, Paul A Voziyan ⁵ ⁶, Gautam Bhave ⁵ ⁶ ⁹ ¹⁰, Loren G Fong ¹, Stephen G Young ¹¹ ¹², Haibo Jiang ¹³ ¹⁴

Affiliations

1 Department of Medicine, University of California, Los Angeles, CA 90095.
2 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095.
3 Centre for Microscopy, Characterisation and Analysis, University of Western Australia, 6009 Perth, Australia.
4 Division of Nephrology, Washington University School of Medicine, St. Louis, MO 63110.
5 Vanderbilt Center for Matrix Biology, Vanderbilt University Medical Center, Nashville, TN 37212.
6 Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
7 Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232.
8 Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232.
9 Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37212.
10 Center for Kidney Disease, Vanderbilt University Medical Center, Nashville, TN 37232.
11 Department of Medicine, University of California, Los Angeles, CA 90095; sgyoung@mednet.ucla.edu haibo.jiang@uwa.edu.au.
12 Department of Human Genetics, University of California, Los Angeles, CA 90095.
13 School of Molecular Sciences, University of Western Australia, 6009 Perth, Australia; sgyoung@mednet.ucla.edu haibo.jiang@uwa.edu.au.
14 Department of Chemistry, The University of Hong Kong, Hong Kong, China.

PMID: 32571911 DOI: 10.1073/pnas.2007749117

Abstract

Bromine and peroxidasin (an extracellular peroxidase) are essential for generating sulfilimine cross-links between a methionine and a hydroxylysine within collagen IV, a basement membrane protein. The sulfilimine cross-links increase the structural integrity of basement membranes. The formation of sulfilimine cross-links depends on the ability of peroxidasin to use bromide and hydrogen peroxide substrates to produce hypobromous acid (HOBr). Once a sulfilimine cross-link is created, bromide is released into the extracellular space and becomes available for reutilization. Whether the HOBr generated by peroxidasin is used very selectively for creating sulfilimine cross-links or whether it also causes oxidative damage to bystander molecules (e.g., generating bromotyrosine residues in basement membrane proteins) is unclear. To examine this issue, we used nanoscale secondary ion mass spectrometry (NanoSIMS) imaging to define the distribution of bromine in mammalian tissues. We observed striking enrichment of bromine (⁷⁹Br, ⁸¹Br) in basement membranes of normal human and mouse kidneys. In peroxidasin knockout mice, bromine enrichment of basement membranes of kidneys was reduced by ∼85%. Proteomic studies revealed bromination of tyrosine-1485 in the NC1 domain of α2 collagen IV from kidneys of wild-type mice; the same tyrosine was brominated in collagen IV from human kidney. Bromination of tyrosine-1485 was reduced by >90% in kidneys of peroxidasin knockout mice. Thus, in addition to promoting sulfilimine cross-links in collagen IV, peroxidasin can also brominate a bystander tyrosine. Also, the fact that bromine enrichment is largely confined to basement membranes implies that peroxidasin activity is largely restricted to basement membranes in mammalian tissues.

Keywords

NanoSIMS imaging; bromine; bromotyrosine; collagen IV; sulfilimine cross-links.

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