Pathophysiology of Transglutaminases Including Factor FXIII

Abstract

Transglutaminases are at least nine enzymes that crosslink a number of proteins. This type of reaction not only enhances or abolishes the original functions of substrate proteins but adds new functions to them. Factor XIII, a plasma transglutaminase circulating in blood as a heterotetramer, consists of two catalytic A subunits and two noncatalytic B subunits. It is a proenzyme to be activated by thrombin in the blood coagulation cascade. It plays an important role(s) in hemostasis, wound healing, and maintenance of pregnancy. Accordingly, a lifelong bleeding tendency, abnormal wound healing, and recurrent spontaneous miscarriage are common symptoms of factor XIII deficiency. Genetic and molecular mechanisms of congenital deficiencies have been analyzed in vitro. The mechanisms of these defects have also been studied in detail using factor XIII gene knockout (KO) mice in vivo. The factor XIII KO mice of either the A or B subunit demonstrated unforeseen cardiac pathologies only in males. Acquired factor XIII deficiency is not uncommon, and one must pay attention to it. Recently, meta-analyses have indicated that the Val34Leu polymorphism of FXIII-A is associated with thrombosis. Emerging data suggest that in addition to its extracellular role in hemostasis FXIII-A may function as a cellular transglutaminase and be involved in certain intracellular processes that include cytoskeletal remodeling and signal transduction.