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Transglutaminases form a family of proteins that have evolved for specialized functions such as protein crosslinking in haemostasis, semen coagulation, or keratinocyte cornified envelope formation. In contrast to the other members of this protein family, tissue transglutaminase is a multifunctional enzyme apparently involved in very disparate biological processes. By virtue of its reciprocal Ca2+-dependent crosslinking activity or GTP-dependent signal transducing activity, tissue transglutaminase exhibits true multifunctionality at the molecular level. The crosslinking activity can subserve disparate biological phenomena depending on the location of the target proteins. Intracellular activation of tissue transglutaminase can give rise to crosslinked protein envelopes in apoptotic cells, whereas extracellular activation contributes to stabilization of the extracellular matrix and promotes cell-substrate interaction. While tissue transglutaminase synthesis and activation is normally part of a protective cellular response contributing to tissue homeostasis, the enzyme has also been implicated in a number of pathological conditions including fibrosis, atherosclerosis, neurodegenerative diseases, celiac disease, and cancer metastasis. This review discusses the role of transglutaminases in extracellular matrix crosslinking with a focus on the multifunctional enzyme tissue transglutaminase.

Tissue transglutaminase (TGase2) is a protein-crosslinking enzyme known to be associated with the in vivo apoptosis program. Here we report that apoptosis could be induced in TGase2 ؊/؊ mice; however, the clearance of apoptotic cells was defective during the involution of thymus elicited by dexamethasone, anti-CD3 antibody, or ␥-irradiation, and in the liver after induced hyperplasia. The lack of TGase2 prevented the production of active transforming growth factor-␤1 in macrophages exposed to apoptotic cells, which is required for the up-regulation of TGase2 in the thymus in vivo, for accelerating deletion of CD4؉CD8؉ cells and for efficient phagocytosis of apoptotic bodies. The deficiency is associated with the development of splenomegaly, autoantibodies, and immune complex glomerulonephritis in TGase2 ؊/؊ mice. These findings have broad implications not only for diseases linked to inflammation and autoimmunity but also for understanding the interrelationship between the apoptosis and phagocytosis process.