Transglutaminase Activity in Cellular and Disease Processes

Transglutaminases are a family of calcium-dependent enzymes that catalyse the formation of covalent isopeptide bonds between glutamine and lysine side chains or deamidate glutamine residues. These post-translational modifications underpin stabilisation of the extracellular matrix, regulation of cell adhesion, modulation of signal transduction and control of cell survival or death. The prototypical enzyme, transglutaminase 2 (TG2), exhibits multiple activities including transamidation, GTPase and scaffold functions, with conformational switching between closed (GTP-bound, non-transamidase) and open (calcium-bound, transamidase) states. In normal physiology, transglutaminase activity facilitates wound repair, tissue architecture and vesicle trafficking. Aberrant activation or overexpression is implicated in diverse pathologies: TG2 is the major autoantigen in coeliac disease, while excessive crosslinking drives tissue fibrosis in kidney, heart and lung, and contributes to vascular complications in diabetes. In cancer, both tissue and extracellular vesicle-associated transglutaminases promote metastatic niche formation and chemoresistance. Emerging work also links transglutaminase-mediated monoaminylation of histones to epigenetic regulation. Given their central role in protein remodelling, transglutaminases are under investigation as diagnostic biomarkers and as targets for selective small-molecule inhibitors with therapeutic promise across fibrotic, metabolic, immune and neoplastic disorders.

Research from Nature Portfolio

Recent studies have elucidated the structural basis of autoantigenicity for transglutaminase 3 in dermatitis herpetiformis. High-resolution crystal structures captured inactive and activated enzyme–substrate complexes, revealing a large conformational rearrangement upon proteolytic cleavage that exposes a β-sheet in the catalytic core. This activated form is specifically recognised by patient-derived autoantibodies, suggesting a mechanism by which B-cell receptors internalise gluten–enzyme complexes to drive antigen presentation and autoantibody production. The work provides atomic-level insight into the interplay between enzyme activation and immune recognition in gluten-triggered pathology.

Transglutaminase Activity in Cellular and Disease Processes publication trend

The graph below shows the total number of articles in transglutaminase activity in cellular and disease processes across all publications each year (not limited to Nature Index journals).

Technical terms

Transamidation: Enzymatic reaction forming an isopeptide bond between glutamine and lysine side chains in proteins.

Deamidation: Enzymatic conversion of a glutamine residue to glutamic acid by removal of an amide group.

Isopeptide bond: Covalent linkage between amino-acid side chains that stabilises protein assemblies and extracellular matrices.

Autoantigen: Self-derived molecule that is aberrantly recognised by the immune system, triggering autoimmunity.

Extracellular vesicle: Membrane-bound particle released by cells to mediate intercellular communication through cargo delivery.

M2 macrophage polarization: Activation state of macrophages induced by anti-inflammatory signals, characterised by tissue remodelling and fibrotic functions.

References

1. Transglutaminase 2 Undergoes a Large Conformational Change upon Activation. PLOS Biology (2007).
2. Autoantibody binding and unique enzyme-substrate intermediate conformation of human transglutaminase 3. Nature Communications (2023).
3. Transglutaminase 2 in diabetes mellitus: Unraveling its multifaceted role and therapeutic implications for vascular complications. Theranostics (2024).
4. Tissue transglutaminase exacerbates renal fibrosis via alternative activation of monocyte-derived macrophages. Cell Death & Disease (2023).
5. Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche. Oncogenesis (2020).
6. Serotonylation: Serotonin Signaling and Epigenetics. Frontiers in Molecular Neuroscience (2019).