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

Abstract

Essentials Plasma Factor XIII, a heterodimer of A and B subunits FXIIIA 2 B 2 , is a transglutaminase enzyme with a well-established role in haemostasis. Cells of bone marrow and mesenchymal lineage express the FXIII-A gene (F13A1) that encodes the cellular form of the transglutaminase, a homodimer of the A subunits, FXIII-A. FXIII-A was presumed to function intracellularly, however, several lines of evidence now indicate that FXIII-A is externalised by an as yet unknown mechanism This review describes the mounting evidence that FXIII-A is a diverse transglutaminase with many intracellular and extracellular substrates that can participate in an array of biological processes. Summary: Factor XIII is a tranglutaminase enzyme that catalyzes the formation of ε-(γ-glutamyl)lysyl isopeptide bonds in protein substrates. The plasma form, FXIII-A 2 B 2 , 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, owing 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 externalized 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, such as wound healing, phagocytosis, and bone and matrix remodeling, reflect its expression in these cell types. This review describes the mounting evidence that this cellular transglutaminase can be externalized, 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.