TGM2 Gene

TGM2 (the transglutaminase 2 gene) is a protein-coding gene located on chromosome 20q11.23. Two transcript variants encoding different isoforms have been found for this gene. The enzyme transglutaminase 2 encoded by this gene acts as a monomer.

The promoter of the TGM2 gene contains a retinoic acid response element (1.7 kb upstream of the initiation site), an interleukin (IL)-6-specific cis-regulatory element (4 kb upstream of the promoter), a TGF-β1 response element and two AP2-like response elements (upstream of the transcription initiation site). Retinoic acid, vitamin D, TGF-β1, IL-6, tumor necrosis factor (TNF), NF-κB, epidermal growth factor (EGF), phorbol esters, oxidative stress and Hox-A7 induce TG2 expression.

Furthermore, the encoded protein is the autoantigen that plays a crucial pathogenetic role in celiac disease.

The functions of TGM2 include GTP binding and protein-glutamine-gamma-glutamyltransferase activity. An important paralog of the TGM2 gene is TGM5.

TGM2 is a calcium-dependent acyltransferase. TGM2 is involved in many biological processes such as bone development, angiogenesis, wound healing, cell differentiation, chromatin modification and apoptosis. TGM2 catalyzes the formation of covalent bonds between peptide-bound glutamine and various primary amines. This generates cross-linked or aminated proteins.

Under physiological conditions, the protein cross-linking activity of TGM2 is inhibited by GTP; the inhibition is reversed by Ca(2+) released in response to various stress factors. When secreted, it catalyzes the cross-linking of extracellular matrix proteins, such as FN1 and SPP1, leading to the formation of scaffolds.

TGM2 also plays a key role during apoptosis by promoting both the cross-linking of cytoskeletal proteins, leading to cytoplasmic condensation, and mediating the cross-linking of extracellular matrix proteins, leading to the irreversible formation of scaffolds that stabilize the integrity of dying cells prior to their elimination by phagocytosis, thereby preventing the leakage of harmful intracellular components. In addition to protein cross-linking, TGM2 can use various monoamine substrates to catalyze a variety of post-translational protein modifications.

• For example, the enzyme mediates the aminylation of serotonin, dopamine, noradrenaline or histamine into glutamine residues of target proteins to generate protein serotonylation, dopaminylation, noradrenalinylation and histaminylation, respectively.
• Mediates protein serotonylation of small GTPases during platelet activation and aggregation, leading to constitutive activation of these GTPases.
• Plays a key role in chromatin organization by mediating serotonylation and dopaminylation of histone H3.
• Catalyzes the serotonylation of 'Gln-5' of histone H3 (H3Q5ser) during differentiation of serotonergic neurons, thereby facilitating transcription.
• Also acts as a protein deamidase by mediating the side chain deamidation of specific glutamine residues of proteins to glutamate.
• Catalyzes the specific deamidation of the protein gliadin, a component of wheat gluten in food.
• Catalyzes the specific deamidation of the protein gliadin, a component of wheat gluten in food. Can also act as an isopeptidase that cleaves the previously formed cross-links.

Diseases associated with TGM2 include:

• dermatitis herpetiformis
• and
• balanitis xerotica obliterans (in this disease, reduced expression of TG1 and TG3 is detectable in affected tissue, with simultaneous overexpression of TG2. TG2 is thought to play a crucial role in triggering and maintaining chronic inflammation in balanitis xerotica obliterans patients (Ientile R et al. 2018).

1. Caputo I et al. (2009) Tissue transglutaminase in celiac disease: role of autoantibodies. Amino Acids 36: 693-699.
2. Korponay-Szabó IR et al (2004) In vivo targeting of intestinal and extraintestinal transglutaminase 2 by coeliac autoantibodies. Gut 53: 641-648.
3. Ientile R et al (2018) Anti-inflammatory and Tissue Regenerative Effects of Topical Treatment with Ozonated Olive Oil/Vitamin E Acetate in Balanitis Xerotica Obliterans. Molecules 23: 645.
4. Lindfors K et al. (2009) A role for anti-transglutaminase 2 autoantibodies in the pathogenesis of coeliac disease? Amino Acids 36: 685-691.
5. Russo T et al (2016) Expression of transglutaminase in foreskin of children with balanitis xerotica obliterans. Int J Mol Sci 17:1551.