Let's cross-link: diverse functions of the promiscuous cellular transglutaminase, factor XIII-A

Factor (F)XIII is a tranglutaminase enzyme that catalyses the formation of ε-(γ-glutamyl)lysyl isopeptide bonds into protein substrates. The plasma form, FXIIIA2 B2 has an established function in hemostasis, where its primary substrate is fibrin. A deficiency in FXIII manifests as a severe bleeding diathesis underscoring its importance in this pathway. The cellular form of the enzyme, a homodimer of the A subunits, denoted FXIII-A, has not been studied in as extensive detail. FXIII-A was generally perceived to remain intracellular, due to the lack of a classical signal peptide for its release. In the last decade emerging evidence has revealed that this diverse transglutaminase can be externalised from cells, by an as yet unknown mechanism, and can cross-link extracellular substrates and participate in a number of diverse pathways. The FXIII-A gene (F13A1) is expressed in cells of bone marrow and mesenchymal lineage, notably megakaryocytes, monocytes/macrophages, dendritic cells, chrondrocytes, osteoblasts and preadipocytes. The biological processes that FXIII-A is coupled with reflect its expression in these cell types, such as wound healing, phagocytosis and bone and matrix remodelling. This review describes the mounting evidence that this cellular transglutaminase can be externalised, usually in response to stimuli, and participate in extracellular cross-linking reactions. A corollary of being involved in these biological pathways is the participation of FXIII-A in pathological processes. In conclusion, the functions of this transglutaminase extend far beyond its role in hemostasis and our understanding of this enzyme in terms of its secretion, regulation and substrates is in its infancy. This article is protected by copyright. All rights reserved.