TGM2

Detailed Information

The TGM2 gene is located on human chromosome 20q11.23 and encodes transglutaminase 2 (TG2), a calcium-dependent acyl transferase with multi-enzyme activity. This enzyme primarily catalyzes the formation of ε-(γ-glutamyl)lysine cross-links between the γ-carboxamide group of glutamine residues in proteins and the ε-amino group of lysine residues, mediating protein cross-linking. It can also catalyze the transacylation of primary amines to glutamine residues in proteins. Additionally, TGM2 has GTPase activity, protein disulfide isomerase activity, and protein kinase activity, participating in multiple cellular processes. Structurally, TGM2 contains an N-terminal β-fold domain, a central catalytic domain, and two C-terminal β-barrel domains. Under physiological conditions, TGM2 exists in a "closed conformation," where the enzyme's active site is masked. When calcium ion concentrations increase, it undergoes a conformational change to the "open" state, exposing the active site. This conformational change allows TGM2 to respond to changes in the intracellular and extracellular environments, precisely regulating its enzymatic activity.

Figure 1. TG2-related signaling pathways in breast cancer metastasis and drug resistance. (Li M, et al., 2024)

Role in Apoptosis

TGM2 plays a key role in apoptosis. On one hand, it catalyzes the cross-linking of cytoskeletal proteins (e.g., actin, filamin) to form insoluble protein networks, maintaining the integrity of the apoptotic cell membrane and preventing intracellular components from leaking and triggering inflammatory responses. On the other hand, TGM2 mediates the cross-linking of extracellular matrix proteins (e.g., fibronectin, osteopontin), forming stable scaffolds that facilitate the efficient clearance of apoptotic cells by phagocytes. In tissue repair, TGM2 accelerates wound healing by cross-linking fibrinogen and collagen. In bone development, TGM2 is involved in regulating bone matrix mineralization, and its absence results in abnormal bone formation.

TGM2 and Epigenetic Regulation

Recent studies have revealed that TGM2 plays a novel role in epigenetic regulation. As an intracellular enzyme that modifies monoamine neurotransmitters, TGM2 catalyzes the covalent attachment of serotonin (5-HT), dopamine, norepinephrine, or histamine to the glutamine residue at position 5 of histone H3 (H3Q5), resulting in serotonination (H3Q5ser), dopaminylation (H3Q5dop), norepinephrination, or histaminylation modifications. During serotoninergic neuron differentiation, TGM2-mediated H3Q5 serotonination promotes the transcription of neurodifferentiation-related genes. In ventral tegmental area (VTA) dopaminergic neurons, TGM2-catalyzed H3Q5 dopaminylation regulates reward system transcriptional plasticity and influences relapse-associated behaviors. These findings tightly link TGM2 to the regulation of neuroplasticity, opening new perspectives for research into neuropsychiatric disorders.

Immunoregulation

In immunoregulation, TGM2 expression in adipose tissue macrophages (ATMs) is crucial for maintaining an anti-inflammatory phenotype. In high-fat diet (HFD)-induced obese mice, the number of TGM2+ ATMs in epididymal white adipose tissue (eWAT) is significantly increased. Mechanistically, TGM2 promotes the production of the anti-inflammatory cytokine IL-10 and inhibits the proliferation of pro-inflammatory MHC IIhi+ ATMs, alleviating adipose tissue inflammation. CRISPR-Cas9-mediated silencing of the Tgm2 gene in bone marrow-derived macrophages (BMMs) results in an enhanced pro-inflammatory phenotype, as LPS-stimulated BMMs secrete more IFN-γ and show reduced expression of the anti-inflammatory markers CD206 and IL-10. In CD11b+ myeloid cell-specific Tgm2 knockout mouse models, adipose tissue inflammation is exacerbated, and serum levels of pro-inflammatory cytokines MCP-1 and TNF-α are elevated, accompanied by more severe obesity, adipocyte hypertrophy, and insulin resistance.

Pathological Mechanisms and Disease Associations

TGM2's role in autoimmune diseases has garnered significant attention. In celiac disease, TGM2 catalyzes the deamidation of gluten proteins (e.g., gliadin), generating negatively charged peptide fragments. These fragments bind with high affinity to HLA-DQ2/8 molecules, activating CD4+ T cell responses and driving mucosal damage. At the same time, the deamidated peptides act as autoantigens, inducing the production of anti-TGM2 autoantibodies, forming a characteristic serological marker. In Henoch-Schönlein purpura (HSP) kidney injury, peripheral blood nucleated cells from HSP nephropathy patients show significantly higher TGM2 mRNA expression levels compared to the non-nephropathy and healthy control groups. Immunohistochemical analysis of kidney tissue shows that TGM2-positive expression in the kidney is significantly higher in HSP nephropathy patients and correlates positively with ISKDC kidney pathology grading, suggesting its involvement in glomerular immune complex deposition and inflammation.

In atopic dermatitis (AD), a team from Fujian Medical University found that although TGM2 mRNA and protein expression in peripheral blood mononuclear cells (PBMCs) of AD patients did not significantly differ from healthy controls, its expression level correlated with specific inflammatory factors: TGM2 mRNA expression positively correlated with IL-4 and P2RX7 mRNA expression (rs values of 0.42 and 0.40, respectively). P2RX7, as an ATP-gated ion channel, can activate TGM2 secretion, participating in skin barrier function regulation. Notably, IL-4 expression in AD patient PBMCs was lower than in the control group, while IL-8 and IL-13 expression was elevated, reflecting a Th2 immune shift, though the role of TGM2 in this process requires further exploration.

Metabolic Diseases and TGM2

TGM2 has been experimentally confirmed to have a protective role in obesity-related metabolic disorders. In HFD-fed obese mice, the number of TGM2+ myeloid cells in eWAT significantly increases, with elevated Tgm2 expression in monocytes, indicating that monocytes are an important source of TGM2+ ATMs. Mechanistically, macrophage-derived TGM2 regulates the inflammatory state of adipose tissue immune cells through paracrine signaling. Co-culturing Tgm2-silenced BMMs with eWAT stromal vascular fraction (SVF) cells results in a reduction in anti-inflammatory CD206+ ATMs and impaired IL-10 production by CD4+ T cells. Exogenous recombinant TGM2 (rTGM2) treatment directly promotes IL-10 secretion in SVF cells from normal diet mice, but this effect is diminished in SVF cells from HFD-fed mice, suggesting that long-term HFD may induce immune cell resistance to TGM2's anti-inflammatory action.

Role of TGM2 in Cancer Progression

TGM2's role in cancer development is complex. On one hand, its protein cross-linking activity promotes extracellular matrix remodeling, creating a favorable microenvironment for tumor metastasis. On the other hand, TGM2 enhances tumor cell drug resistance by activating pro-survival signals such as NF-κB. Overexpression of TGM2 is associated with aggressive phenotypes in various cancers, including gastric cancer, ovarian cancer, and colorectal cancer. Notably, TGM2 exists in two splice variants: the full-length isoform (TGM2-L) primarily participates in protein cross-linking and cell adhesion, while the shorter isoform (TGM2-S) exhibits a pro-apoptotic effect independent of its enzymatic activity, potentially inhibiting tumor progression. This isoform-specific functional differentiation adds complexity to TGM2's role in cancer.