Role of Hypohalous Acids in Basement Membrane Homeostasis

Abstract

Significance: Basement membranes (BMs) are sheet-like structures of specialized extracellular matrix that underlie nearly all tissue cell layers including epithelial, endothelial, and muscle cells. BMs not only provide structural support but are also critical for the development, maintenance, and repair of organs. Animal heme peroxidases generate highly reactive hypohalous acids extracellularly and, therefore, target BMs for oxidative modification. Given the importance of BMs in tissue structure and function, hypohalous acid-mediated oxidative modifications of BM proteins represent a key mechanism in normal development and pathogenesis of disease. Recent Advances: Peroxidasin (PXDN), a BM-associated animal heme peroxidase, generates hypobromous acid (HOBr) to form sulfilimine cross-links within the collagen IV network of BM. These cross-links stabilize BM and are critical for animal tissue development. These findings highlight a paradoxical anabolic role for HOBr, which typically damages protein structure leading to dysfunction.

Critical issues: The molecular mechanism whereby PXDN uses HOBr as a reactive intermediate to cross-link collagen IV, yet avoid collateral damage to nearby BM proteins, remains unclear.

Future directions: The exact identification and functional impact of specific hypohalous acid-mediated modifications of BM proteins need to be addressed to connect these modifications to tissue development and pathogenesis of disease. As seen with the sulfilimine cross-link of collagen IV, hypohalous acid oxidative events may be beneficial in select situations rather than uniformly deleterious. Antioxid. Redox Signal. 27, 839-854.

Keywords: basement membrane; hypobromous acid; hypohalous acid; peroxidase; peroxidasin.

FIG. 1.

Major types of ECM. Schematic representation of the two main types of ECM, the interstitial matrix and the BM. The interstitial matrix surrounds cells and is composed of mostly collagen I, fibronectin, proteoglycans, glycosaminoglycans, and elastin. The BM underlies most epithelial, endothelial, and muscle cells. It is composed mostly of collagen IV, laminin, perlecan, collagen XVIII, and nidogen. Both types of ECM provide cells with a scaffold upon which to adhere or embed, while helping to regulate cellular processes such as growth, migration, and differentiation. BM, basement membrane; ECM, extracellular matrix. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

The major components of basement membranes. Schematic representation of the domain structure for the main components of BM: laminin, type IV collagen, nidogen, agrin, collagen XVIII, and perlecan. Arrows indicate known binding interactions between BM components. HS, heparin sulfate; NtA, N-terminal agrin domain; F, folstatin-like repeats; SEA, sea urchin sperm protein, enterokinase, and agrin domain; LN domain, laminin N-terminal domain; LCC, laminin coiled-coil domain; LG, laminin globular domain; Tsp1, trombospondin-1-like; G, globular-like domains; N-CAM, neural cell adhesion molecule; LDL, low-density lipoprotein receptor; Ig, immunoglobulin repeats; NC1, noncollagenous domain; 7S, N-terminal “7S” domain. A portion of this figure was adapted from Miner (67) with permission from Elsevier. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

Evolution of animal peroxidases. The ancestral animal heme peroxidase found in Cnidaria is PXDN. The addition of two Ig domains and the vWFC domain occurs in lower invertebrates. PXDN likely gave rise to TPO through gene duplication, deletion of noncatalytic domains, and fusion with a TM domain. LPO, EPO, and MPO were likely the result of successive gene duplications after the loss of the TM domain found in TPO. This figure was adapted with permission from work originally published by Ero-Tolliver et al. (25) ©2015 by American Society for Biochemistry and Molecular Biology. EPO, eosinophil peroxidase; PXDN, peroxidasin; LPO, lactoperoxidase; MPO, myeloperoxidase; TPO, thyroid peroxidase; TM, transmembrane; vWFC, von Willebrand factor type C. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

Oxidation reactions of animal heme peroxidases in tissues. PXDN found in basement membranes generates HOBr to form sulfilimine (S = N) cross-links in collagen IV. Activated fibroblasts may also secrete PXDN into interstitial matrix, whereas MPO and EPO are released from activated, infiltrating leukocytes. NADPH oxidases generate superoxide (O₂^{. −}), which dismutates into hydrogen peroxide, a substrate along with halide (Br⁻ and Cl⁻) or pseudohalide (SCN⁻) anions for peroxidase generation of hypohalous acids. Whether intracellular hydrogen peroxide may act as a substrate extracellularly is unclear. PXDN, EPO, and MPO generate HOSCN and HOBr, whereas only MPO produces HOCl in appreciable quantities. HOBr, hypobromous acid. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 5.

Model for PXDN and HOBr-mediated sulfilimine bond formation in collagen IV. Schematic representation of oxidation of bromide to form HOBr that acts as a reactive intermediate to form sulfilimine cross-links in collagen IV via a bromosulfonium intermediate at methionine 93 of the collagen IV NC1 hexamer. This figure was adapted from work originally published by McCall et al. (72) with permission from Elsevier. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 6.

Preference of HOBr over HOCl for sulfilimine bond formation in collagen IV. A model of the oxidative formation of a sulfilimine bond versus the “dead-end” product methionine sulfoxide. The chlorosulfonium intermediate at methionine 93 preferentially undergoes nucleophilic attack by solvent water, whereas the bromosulfonium intermediate tends to react with the juxtaposed lysine nitrogen. k_{S = O} and k_{S = N} denote rate constants in the formation of sulfoxides and sulfilimines, respectively. This figure was adapted from work originally published by McCall et al. (72) with permission from Elsevier. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars