Alternative RNA splicing of leucocyte tissue transglutaminase in coeliac disease

Abstract

Tissue transglutaminase is a ubiquitous and multifunctional protein that contributes to several processes such as apoptosis/survival, efferocytosis, inflammation and tissue repairing under physiological and pathological conditions. Several activities can be associated with well-established functional domains; in addition, four RNA alternative splice variants have been described, characterized by sequence divergences and residues deletion at the C-terminal domains. Tissue transglutaminase is recognized as the central player in the physiopathology of coeliac disease (CD) mainly through calcium-dependent enzymatic activities. It can be hypothesized that differential regulation of tissue transglutaminase splice variants expression in persons with CD contributes to pathology by altering the protein functionality. We characterized the expression pattern of RNA alternative splice variants by RT-PCR in peripheral cells from patients with CD under free gluten diet adhesion; we considered inflammatory parameters and specific antibodies as markers of the stage of disease. We found significant higher expression of both the full length and the shortest C-truncated splice variants in leucocytes from patients with CD in comparison with healthy individuals. As tissue transglutaminase expression and canonical enzymatic activity are linked to inflammation, we studied the RNA expression of inflammatory cytokines in peripheral leucocytes of persons with CD in relation with splice variants expression; interestingly, we found that recently diagnosed patients showed significant correlation between both the full length and the shortest alternative spliced variants with IL-1 expression. Our results points that regulation of alternative splicing of tissue transglutaminase could account for the complex physiopathology of CD.

Differential Expression of Tissue Transglutaminase Splice Variants in Peripheral Blood Mononuclear Cells of Primary Progressive Multiple Sclerosis Patients

“…Still, full-length TG2 (V1) was the highest expressed, which is in line with what has been shown before in polymorphonuclear cells, lymphocytes, monocytes and other cell lines [8,13]. The splice variants V4a and V4b were expressed in PBMCs but their expression level was lower than that of full-length TG2 mRNA which is different from what has been shown before in leucocytes [13,14].…”

“…By displaying an alternative C-terminus splicing (contains the GTP binding domain), the four splice variants of TG2 can escape physiological regulation of its transamidation activity [9]. The expression levels of these variants are found to be altered in several diseases [10,13] which might indicate that under pathological conditions, their role could be due, at least partly, to a relative low intracellular Ca 2+ concentration needed for their activation. In PP-MS, we recently observed that total TG2 expression in PBMCs is relatively high.…”

“…Interestingly, this variant has also been described to have opposite effects on cells as it was found to induce cell differentiation in neuroblastoma cells but cell death in NIH3T3 fibroblasts, unlike the full-length TG2 which acted as repressor of differentiation in neuroblastoma cells and growth-inducer in NIH3T3 cells [11,12]. V3 (TGM2_V3, 38 kDa) mRNA was found to be significantly increased in leukocytes of coeliac disease patients compared to healthy control (HC) subjects, thus suggesting a role in this disease [13]. V4a and V4b mRNA (TGM2_V4a and TGM2_V4b, 75 kDa and 70 kDa, respectively) are predominantly expressed in leukocytes [14] but their function is unknown.…”

The Role of Tissue Transglutaminase in Cancer Cell Initiation, Survival and Progression

“…The so-called short isoform (TGH) has been related to neurodegenerative disorders [46] and to neuroblastoma cell differentiation [36]. Recent data suggests that increased expression of the TGH2 variant may contribute to complex celiac disease physiopathology [47]. Two additional C-terminal truncated isoforms (tTGv1 or TGM2_v4a and tTGv2 or TGM2_v4b) have been identified in human aortic vascular smooth muscle cells and leukocytes [48].…”

Hypoxia and inflammation conditions differentially affect the expression of tissue transglutaminase spliced variants and functional properties of extravillous trophoblast cells

“…20,27,28 In addition, upregulation of certain spliced variants correlated with central nervous system pathologies 27 and autoimmune diseases. 29,30 In placenta TG2 is expressed in stromal cells and trophoblast during first trimester and term pregnancy, under progesterone control. [31][32][33] TG2 participates in decidualization 31 and trophoblast physiology by both TGase activity and adhesive functions.…”