Tissue Transglutaminase but Not Microbial Transglutaminase Is Inhibited by Exogenous Oxidative Substances in Celiac Disease.

Sebastian Stricker,Klaus-Peter Zimmer,Jan De Laffolie,Silvia Rudloff

doi:10.3390/ijms23042248

Sebastian Stricker, Klaus-Peter Zimmer + Show 2 more

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https://doi.org/10.3390/ijms23042248

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Abstract

Enzymatic modification of gliadin peptides by human transglutaminase 2 (TG2) is a central step in celiac disease (CD) pathogenesis. Microbial transglutaminase (mTG) mimics the enzymatic function of TG2 and might play a role in CD. TG2 is inhibited by endogenous oxidative endoplasmic reticulum-resident protein 57 (ERp57), but data about mTG are lacking. We investigated the localization of ERp57 in duodenal biopsies and examined inhibition of TG2, and mTG by competitive, and oxidative molecules. Localization of ERp57 was investigated in duodenal biopsies from CD, and control patients by electron microcopy. Inhibition of TG2 and mTG was analyzed on an in vitro level using a photometric assay. ERp57 was observed within the lamina propria and its abundance within the endoplasmic reticulum (ER) was reduced in CD patients. TG2 was oxidatively inhibited by up to 95% by PX12 (p < 0.001) and L-cystine (p < 0.001), whereas mTG remained unaffected. The reduced presence of ERp57 within the ER of CD biopsies suggests a regulatory function of this protein within CD pathogenesis. PX12 and L-cystine oxidatively inhibit TG2 and might serve as treatment options in CD. mTG is poorly regulated and could contribute to the accumulation of immunogenic peptides within the gut with potential pathogenic effects.

Highlights

Vittoria Barone and Celiac Disease (CD) is a frequent chronic inflammatory disorder triggered by the ingestion of gliadin and related prolamins in genetically predisposed individuals carrying the HLA DQ2/8 genotype [1]
As recent evidence has shown that endoplasmic reticulum-resident protein 57 (ERp57) inhibits extracellular transglutaminase 2 (TG2) activity by oxidation, we determined its localization and distribution within human intestinal biopsies of CD patients and controls
Central aspects of CD pathogenesis such as enzymatic modification of gliadin peptides by TG2 are well understood, it is still open as to why only a small proportion of those who are genetically predisposed suffer from the disease [25]

Summary

Introduction

Vittoria Barone and Celiac Disease (CD) is a frequent chronic inflammatory disorder triggered by the ingestion of gliadin and related prolamins in genetically predisposed individuals carrying the HLA DQ2/8 genotype [1]. One central step in its pathogenesis is de- and transamidation of gliadin peptides by tissue transglutaminase (TG2), the recognized autoantigen of the disease [2]. This enzymatic modification markedly increases the immunogenic properties of those gliadin peptides, and is a prerequisite for any subsequent antigen presentation resulting in a TH1 -mediated immune response [1–4]. In addition to TG2, microbial transglutaminase (mTG) was recently suggested to take part in CD pathogenesis, as it is able to de- and transamidate the same glutamine residues within gliadin peptides, rendering them immunogenic for gluten-specific T cells [5–7]. Though enzymatic activity of mTG is abolished during food processing, its usage could create immunogenic epitopes and complexes within food stuffs. MTG may be released in an active form by our intestinal microbiota (e.g., streptomycetes), contributing additional transglutaminase activity to the gut lumen [10]

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