Abstract
Type 2 transglutaminase (TG2) is a ubiquitous enzyme able to modify gliadin peptides introduced into the organism through the diet. By means of its catalytic activity, TG2 seems to have an important pathogenetic role in celiac disease (CD), an inflammatory intestinal disease caused by the ingestion of gluten-containing cereals. A strong autoimmune response to TG2 characterizes CD development. Anti-TG2 antibodies specifically derange the uptake of the α-gliadin peptide 31–43 by control, but not by celiac dermal fibroblasts, underlying some different constitutive features regarding TG2 in healthy and celiac subjects. Our aim was to investigate whether these differences depended on a different TG2 subcellular distribution and whether peptide 31–43 differentially regulated TG2 expression and activity in cells of the two groups of subjects. We found that TG2 was more abundantly associated with membranes of celiac fibroblasts than of control cells, in particular with the early endosomal and autophagic compartments. We also found that peptide 31–43 differentially affected TG2 expression and activity in the two groups of cells, activating TG2 more in control than in celiac cells and inducing TG2 expression in celiac cells, but not in control ones. The different TG2 subcellular localization and the different way the peptide 31–43 modulates TG2 activity and availability into control and CD cells suggested that TG2 is involved in the definition of a constitutive CD cellular phenotype, thus having an important and still undefined role in CD pathogenesis.
Highlights
Type 2 transglutaminase (TG2) is a ubiquitous multifunctional protein belonging to a family of cross-linking enzymes widely distributed in animals, plants, and microorganisms [1]
We first verified the efficacy of the fractionating protocol on a celiac disease (CD) sample (Figure 1), we focused our attention on how TG2 is relatively more abundant in cytosol or membrane fractions of four control and four celiac samples
Western blot analysis showed that the amount of cytosolic TG2 was slightly lower in CD cells than in controls, whereas TG2 associated with membrane sheets did not vary between the two groups (Figure 2)
Summary
Type 2 transglutaminase (TG2) is a ubiquitous multifunctional protein belonging to a family of cross-linking enzymes widely distributed in animals, plants, and microorganisms [1]. TG2 may exert signaling/scaffolding/adapter functions, which are independent of its enzymatic activities, both inside and outside the cell [3]. All these enzymatic and non-enzymatic functions are finely tuned by TG2 localization into the cell (nucleus, cytosol, mitochondria, membrane inner face, cell surface, extracellular environment), and by the availability of enzymatic regulators (mainly Ca2+ and GTP) and of substrates, as well as by the interaction with other protein partners [2,3,4,5]. TG2 takes part in many biological processes linked to cell survival, differentiation, death, and response to several kinds of stresses [3,6]. Given the crucial regulatory function of TG2 in cell life and death, it plays a key role in several pathologic conditions (cancer, neurodegenerative disorders, fibrosis, etc.) [7,8,9]
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