Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders

Abstract

The human transglutaminase (TG) family consists of a structural protein, protein 4.2, that lacks catalytic activity, and eight zymogens/enzymes, designated factor XIII-A (FXIII-A) and TG1-7, that catalyze three types of posttranslational modification reactions: transamidation, esterification, and hydrolysis. These reactions are essential for biological processes such as blood coagulation, skin barrier formation, and extracellular matrix assembly but can also contribute to the pathophysiology of various inflammatory, autoimmune, and degenerative conditions. Some members of the TG family, for example, TG2, can participate in biological processes through actions unrelated to transamidase catalytic activity. We present here a comprehensive review of recent insights into the physiology and pathophysiology of TG family members that have come from studies of genetically engineered mouse models and/or inherited disorders. The review focuses on FXIII-A, TG1, TG2, TG5, and protein 4.2, as mice deficient in TG3, TG4, TG6, or TG7 have not yet been reported, nor have mutations in these proteins been linked to human disease.

Positional cloning and next-generation sequencing identified a TGM6 mutation in a large Chinese pedigree with acute myeloid leukaemia

“…The upregulation of TGM2 and intratumour TGM2 injections inhibit tumour growth in mice. 16 The reduction or loss of TGM3 expression is common in oesophageal, laryngeal, oral, head and neck squamous cell carcinomas, partially due to its important role in the regulation of stratified squamous epithelia differentiation. 20 Research on FXIII-A-/-mice suggests that factor XIII transglutaminase supports haematogenous tumour cell metastasis.…”

“…16 Several studies demonstrate that retinoic acid (RA)-induced differentiation of myeloid leukaemia cell lines, such as HL60, HEL and THP1, is frequently accompanied by a marked increase in transglutaminase activity, whereas transglutaminase is nearly undetectable before RA treatment in these cell lines. The knockdown of transglutaminase expression using specific siRNA or a transglutaminase inhibitor abrogates the effect of RA.…”

“…Sequence alignments by Promals3D revealed that TGM6 was highly similar to TGM2 and TGM3, which therefore can be used as templates for TGM6 modelling. We observed the L517W mutation located in the first b-barrel domain of TGM6 molecular structure (Supplementary Figure 2), which was important for the conformational transition from an inactive compact form to an active, extended ellipsoid structure 16 that exposes the TGM catalytic core. In addition, this Figure 2 LOD plots for chromosome 20.…”

Nouvelles fonctions de la peptideN-glycanase indépendantes de sa capacité de déglycosylation

“…La comparaison de la séquence peptidique de ScPng1p avec celle d'un membre de la famille des transglutaminases (le facteur XIIIa) a permis de mettre en exergue la conservation de nombreux acides aminés [9], dont ceux qui correspondent à la triade catalytique des transglutaminases : Cys191, His218 et Asp235 [10]. Cette triade catalytique et les motifs CXXC, qui sont des sites de liaison du zinc [11], jouent un rôle important dans l'activité de la PNGase.…”

“…De nombreuses maladies neurodégénératives sont associées à un dysfonctionnement du contrôle de qualité qui joue un rôle déterminant dans l'accumulation des protéines mal repliées et dans l'évolution de la maladie. Il est donc légitime de se demander si un dysfonctionnement de cette enzyme ne peut pas être associé à une neurodégénérescence comme cela avait été observé dans les dysfonctionnements de certains représentants de la famille des transglutaminases [10]. Alors que l'expression de Ngly1p est ubiquiste, il est éga-lement surprenant que certains organes (comme le foie ou le système nerveux central) soient plus particulièrement affectés.…”