Insights into Transglutaminase 2 Function Gained from Genetically Modified Animal Models

Iismaa, Siiri E.

doi:10.1007/978-4-431-55825-5_4

Cited by 2 publications

(3 citation statements)

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“…However, a definite correlation between TG function or deficiency and a specific pathology has been consistently demonstrated in only a few cases, examples of which are discussed below. Knockout mouse models have been useful to correlate the functional roles of FXIIIA, TG1, TG2, TG3, TG4, and protein 4.2 with various physiologic and disease mechanisms (7,8). No studies of knockout mice for TG5, TG6, or TG7 have been reported.…”

Section: Tgs and Diseasementioning

confidence: 99%

“…Shortcomings, in terms of reliability and reproducibility of mouse studies, alluded to above, are evident in some contradictory studies that have been reported for TG2 knockout mice, particularly in the areas of apoptosis, mitochondrial function, vascular remodeling, and neurodegenerative diseases (7,8). With respect to the latter, for example, despite TG2 being implicated in Huntington's disease pathogenesis for almost 20 yr, recent evidence from genetic ablation of TG2 in 2 different Huntington's disease models, where experiments were performed according to recommended guidelines for animal husbandry, indicates that TG2 deletion does not improve motor, cognitive, molecular, histologic, or lifespan phenotypes and is thus not an important factor in Huntington's disease pathology (8,47). However, neither the presence nor activities of TG isozymes were measured to rule out possible intracellular induction of other TG family members, such as TG1, that may contribute to intracellular crosslinking processes.…”

Section: Tg-mediated Crosslinking Of Crystallins Contributes To the F...mentioning

confidence: 99%

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Transglutaminase diseases: from biochemistry to the bedside

Lóránd

Iismaa

2018

The FASEB Journal

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In humans, 9 members of the transglutaminase (TG) family have been identified, of which 8 [factor XIII (FXIII)A and TG1–TG7] catalyze post‐translational protein‐modifying reactions, and 1 does not (protein 4.2). The TG enzymatic activities considered in our discussion of human disease include deamidation of glutamine (Gln) residues, amine incorporation into Gln residues, and protein crosslinking. Except for TG7, which remains poorly studied, all individual TG members have been correlated with disparate human diseases that arise from either TG function or lack of function. Loss of TG function is associated with numerous orphan diseases that affect a relatively small number of individuals: loss of FXIIIa (transamidase‐activated form) crosslinking leads to defects in blood coagulation in FXIII deficiency; loss of TG1 and TG5 cross linking leads to defects in epidermal cornification in lamellar ichthyosis and acral peeling skin syndrome, respectively; loss of TG3 crosslinking in hair‐cuticle formation leads to uncombable hair syndrome; the predicted loss of TG6 crosslinking leads to spinocerebellar ataxia‐35; and loss of the structural erythrocyte membrane protein, protein 4.2, leads to hereditary spherocytosis type 5. The enzymatic activity of TG2 is involved in the exacerbation of celiac disease and in at least 1 case of hemoglobinopathy, characterized by shortened erythrocyte lifespan. TGs are also autoantigens in a number of immune diseases, resulting in the production of autoantibodies against FXIIIa in acquired FXIII deficiency, TG2 in celiac disease, TG3 in dermatitis herpetiformis, TG4 in autoimmume polyglandular syndrome type 1, and TG6 in gluten axonal neuropathy and gluten ataxia. Much still remains to be learned and confirmed with respect to disease mechanisms, particularly with respect to TG‐related immune diseases, in which development of isozyme‐specific inhibitors may be useful for treatment.—Lorand, L., Iismaa, S. E. Transglutaminase diseases: from biochemistry to the bedside. FASEB J. 33, 3–12 (2019). http://www.fasebj.org

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Section: Tgs and Diseasementioning

confidence: 99%

Section: Tg-mediated Crosslinking Of Crystallins Contributes To the F...mentioning

confidence: 99%

Transglutaminase diseases: from biochemistry to the bedside

Lóránd

Iismaa

2018

The FASEB Journal

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“…Targeted mutant mice, such as those with a gene knockout (KO), play a vital role in understanding the integrated physiological and pathological functions of a protein in a tissue-specific context [ 89 ]. Three TG2 KO mouse lines [ 90 , 91 , 92 ] were generated using genomic DNA from the 129 sub-strain to target the catalytic domain of the Tgm2 gene.…”

Section: Targeting Tg2 In Inflammation and Sepsis: Evidence From Kmentioning

confidence: 99%

Transglutaminase 2 as a Marker for Inflammation and Therapeutic Target in Sepsis

Qin

Furutani

2021

IJMS

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Sepsis results in lethal organ malfunction due to dysregulated host response to infection, which is a condition with increasing prevalence worldwide. Transglutaminase 2 (TG2) is a crosslinking enzyme that forms a covalent bond between lysine and glutamine. TG2 plays important roles in diverse cellular processes, including extracellular matrix stabilization, cytoskeletal function, cell motility, adhesion, signal transduction, apoptosis, and cell survival. We have shown that the co-culture of Candida albicans and hepatocytes activates and induces the translocation of TG2 into the nucleus. In addition, the expression and activation of TG2 in liver macrophages was dramatically induced in the lipopolysaccharide-injected and cecal ligation puncture-operated mouse models of sepsis. Based on these findings and recently published research, we have reviewed the current understanding of the relationship between TG2 and sepsis. Following the genetic and pharmacological inhibition of TG2, we also assessed the evidence regarding the use of TG2 as a potential marker and therapeutic target in inflammation and sepsis.

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Insights into Transglutaminase 2 Function Gained from Genetically Modified Animal Models

Cited by 2 publications

References 116 publications

Transglutaminase diseases: from biochemistry to the bedside

Transglutaminase diseases: from biochemistry to the bedside

Transglutaminase 2 as a Marker for Inflammation and Therapeutic Target in Sepsis

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