Tải bản đầy đủ - 0 (trang)
4 Post-Translational Modifications (PTMs) of TG2 in Response to Oxidative StressPost-Translational Modifications (PTMs)

4 Post-Translational Modifications (PTMs) of TG2 in Response to Oxidative StressPost-Translational Modifications (PTMs)

Tải bản đầy đủ - 0trang


E.M. Jeong and I.-G. Kim

Fig. 14.4 ROS induce post-translational modifications of TG2. (1) Intramolecular disulfides;

oxidative stress induces the formation of vicinal disulfide bond (Cys230-Cys370) in TG2, which

facilitates another vicinal disulfide (Cys370-Cys371) formation (Bogeski et al. 2011). TG2 with

vicinal disulfides is inactive, but can be reduced and activated by thioredoxin, which may be

secreted from IFN-γ-stimulated monocytes or possibly the celiac intestinal mucosa (Jin

et al. 2011). S-Glutathionylation at Cys230 of TG2 is suspected to be a transient modification to

promote vicinal disulfide formation (Bogeski et al. 2011). (2) S-Nitrosylation; under nitrosative

stress, TG2 can be modified by S-nitrosylation at up to 15 cysteine residues, resulting in its

inactivation in vitro and in vivo (Lai et al. 2001; Santhanam et al. 2010). (3) Ubiquitination; a

high level of ROS induces intracellular calcium overload that promotes TG2 degradation via the

ubiquitin proteasome pathway (Jeong et al. 2009). (4) SUMOylation; CFTRΔF508-induced ROS

induce TG2 interaction with PIASy, a SUMO E3 ligase. Consequently, TG2 is modified by

SUMO-1, which increases TG2 protein level via inhibition of ubiquitin proteasomal degradation,

favoring TG2 activation (Luciani et al. 2009). ROS reactive oxygen species, RNS reactive nitrogen

species, [Ca2+]i intracellular calcium concentration, GSH reduced glutathione, GSSG oxidized

glutathione, IFN-γ interferon gamma, PTM post-translational modification, PIASy protein inhibitor of activated STAT y, SUMO-1 small ubiquitin-like modifier-1

reagents such as dithiothreitol (DTT), whereas alkylated TG2 was not. The active

site Cys277 was not involved in the oxidation process. They suggested that TG2

might be inactivated through the formation of an intramolecular disulfide bridge

between certain regulatory cysteine residues.

TG2 conformation changes substantially upon activation. TG2 exhibits an open

form during calcium-mediated activation, however, it presents a closed inactive

form that is induced by binding to the nucleotide (see Chap. 1). Recently, an

intramolecular disulfide bond between Cys370 and Cys371 was found by solving

crystal structures of the open form of TG2 in complex with a reactive gluten peptide

mimetic inhibitor (Pinkas et al. 2007). Meanwhile, the x-ray crystal structures of

GTP or ATP-bound TG2, which have closed forms, revealed another vicinal

disulfide between Cys230 and Cys370 (Han et al. 2010; Jang et al. 2014). However,

the vicinal disulfides did not exist in the crystal structures of the GDP-bound form

(Liu et al. 2002). It seems that Cys370-Cys371 stabilizes the open structure of TG2

and Cys230-Cys370 stabilizes the nucleoside triphosphate binding closed conformation of TG2. Notably, residues of Cys230, Cys370, and Cys371 are proximate to each

other in the crystal structures of both the open and closed forms of TG2


Regulation of Transglutaminase 2 by Oxidative Stress


(Jang et al. 2014; Pinkas et al. 2007). This suggests that Cys370 can readily change

neighboring cysteine residues in the process of TG2 oxidation.

Sollid and colleagues eventually proved that Cys230, Cys370, and Cys371 are bona

fide redox-sensitive cysteine residues and disulfide bond formation between these

residues renders TG2 inactive (Stamnaes et al. 2010). They showed that oxidative

stress induces Cys230-Cys370 disulfide bond formation, which facilitates the Cys370Cys371 disulfide bond, stabilizing the open structure (Fig. 14.4). Given that Sglutathionylation at Cys230 is observed early on in the oxidation process, vicinal

disulfide bond formation might be initiated by Cys230 oxidation (Fig. 14.4),

suggesting that Cys230 works as a redox sensor. Interestingly, Cys230 is not conserved in other TG isotypes. Thus, TG2 might be uniquely regulated by redox in

this manner. Khosla and his colleagues calculated the redox potential of these

redox-sensitive triad cysteines in human TG2 to be approximately À190 mV (Jin

et al. 2011). This makes disulfide bond formation between TG2 cysteine residues a

biologically relevant regulatory mechanism. Under normal conditions, the redox

potential of the extracellular space through GSH/GSSG and cysteine/cystine redox

couples is approximately À140 mV and À80 mV, respectively (Banerjee 2012).

This implies that most of the secreted TG2 is probably oxidized and inactivated.

However, in inflamed regions, TG2 can be reduced and activated by an increase of

extracellular thioredoxin, which is secreted from monocytes triggered by interferon-γ (Jin et al. 2011). Because thioredoxin has lower redox potential (À230 mV)

than the TG2 reactive cysteine residues (Watson et al. 2003), it has been proposed

that this is the key activation mechanism of extracellular TG2 under pathological

conditions, especially in celiac disease.

Apparently, the redox regulation should work in the endoplasmic reticulum

(ER) as well. ER contains 100–500 μM of free Ca2+ (Monteith et al. 2007) which

is enough to activate TG2 (see Sect. 14.5.1). However, the ER redox potential is

between approximately À190 and À130 mV (Sarkar et al. 2013) and it is possible

that unwanted TG2 activation is prevented by the oxidation of the reactive cysteines

in the ER. On the other hand, it has been well proven that intracellular TG2 is

aberrantly activated under oxidative environments, as they are generally favorable

for vicinal disulfide formation. Thus, it is not clear whether the vicinal disulfide

bonds control TG2 in the cytosol and other cell organelles.

14.4.2 S-Nitrosylation

It is well known that the thiol group of cysteine residues in protein can be reversibly

oxidized by reactive nitrogen species (RNS) as well as ROS. TG2 can be modified

with S-nitrosylation by RNS in vitro and in vivo, inhibiting its crosslinking activity

(Fig. 14.4) (Lai et al. 2001; Santhanam et al. 2010). NO is also known to inhibit

non-classical secretion of TG2 into the extracellular space in human aortic endothelial cells (Santhanam et al. 2010), Swiss 3T3 fibroblasts (Telci et al. 2009), and

IMR90 fibroblasts (Jandu et al. 2013), which suggests that S-nitrosylation may be


E.M. Jeong and I.-G. Kim

one of the mechanisms involved in inhibiting extracellular TG2 (Santhanam

et al. 2011). In a model of age-associated vascular stiffness, it has been demonstrated that the level of S-nitrosylated TG2 is reduced in the aorta of aged mice. This

is due to a decrease of NO production, leading to vascular stiffness by an increase of

TG2-mediated extracellular crosslinking (Santhanam et al. 2010). In addition to Snitrosylation of cysteine residues, NO is also known to increase nitrosylation of

tyrosine residues in TG2 (Telci et al. 2009). Given that TG2 has a tyrosine residue

that is critical (Tyr274 in human TG2) for activation (Begg et al. 2006a), TG2 can be

inhibited by tyrosine nitrosylation (Telci et al. 2009) as well as S-nitrosylation

under nitrosative stressed conditions. However, the biological role(s) of tyrosine

nitrosylation in TG2 is/are not well known. Moreover, whether S-nitrosylation is

directly involved in TG2 externalization remains unknown (Santhanam et al. 2011).

Hence, the role of nitrosylation in TG2 regulation needs to be clarified.

14.4.3 Ubiquitination

In response to low or moderate oxidative stress, the TG2 expression level increases

via its promoter activation (Sect. 14.3) or SUMOylation (Sect. 14.4.4), which

favors its intracellular enzymatic activation. TG2 activity may inhibit apoptosis

through crosslinking of caspase-3 and IκBα (Jang et al. 2010); however, under high

or incessant oxidative conditions, TG2 can promote cell death, probably due to

accumulation of crosslinked cellular proteins (Fesus and Tarcsa 1989). Thus, TG2

activity should be negatively regulated to avoid molecular aggregation under

extremely stressed situations. One powerful mechanism to achieve this is

ubiquitin-dependent proteasomal degradation. High oxidative stress triggers intracellular calcium overload that renders TG2 inactive via the polyubiquitination and

proteasomal degradation pathway (Jeong et al. 2009) (Fig. 14.4). However, the

ubiquitination sites in TG2 and the associated E3 ligase have not yet been


14.4.4 SUMOylation

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride ion

channel formed at the apical membrane of epithelial cells in many organs including

the lung, kidney, intestine, and pancreas. Mutations in the CFTR gene are the major

cause of cystic fibrosis. CFTRΔF508, a phenylalanine-deleted CFTR mutant at

position 508, is the most common mutation to cause cystic fibrosis (Cutting

2015). CFTRΔF508 is retained in the ER due to its misfolded structure, which in

turn leads to ER stress and an increase in the production of ROS. Mairui and

colleagues showed that CFTRΔF508-mediated ROS induce the interaction of TG2

with one of the protein inhibitors of activated STAT (PIAS) proteins, PIASy. It is a


Regulation of Transglutaminase 2 by Oxidative Stress


small ubiquitin-like modifier (SUMO) E3 ligase and it drives TG2 to be modified by

SUMO-1 (Fig. 14.4) (Luciani et al. 2009). SUMOylation in TG2 hinders its

ubiquitination and proteasomal degradation like many other SUMOylated proteins

such as nuclear factor (NF)-κB essential modulator (NEMO), IκBα, and proliferating cell nuclear antigen (PCNA) (Geiss-Friedlander and Melchior 2007). Therefore,

TG2 expression can be sustained at high levels in epithelial cells of cystic fibrosis

patients harboring the CFTRΔF508 mutation.

SUMOylated TG2 plays a pathogenic role in cystic fibrosis by modulating IκBα,

PPARγ, and Beclin 1 pathways. TG2 crosslinks PPARγ and probably IκBα to

prevent their modification by SUMO-1. This results in their degradation via the

ubiquitin proteasome system, as well as in aberrant activation of the NF-κB signal

and an unrestrained inflammatory response (Luciani et al. 2009; Maiuri et al. 2008).

Additionally, TG2 also catalyzes crosslinking of Beclin 1, a mammalian homolog

of the yeast autophagy-related gene (Atg) 6, which plays a central role in the initial

stages of autophagy (Marino et al. 2014). TG2-mediated crosslinking of Beclin

1 promotes the sequestration of Beclin 1-VPS34 complex into HDAC6-positive

aggresomes, hindering the autophagy process (Luciani et al. 2010a). Overall, TG2

SUMOylation exacerbates cystic fibrosis by promoting inflammation and inhibiting

autophagy. Thus, it has been suggested that the SUMOylation-mediated TG2

activation pathway can be an effective target for cystic fibrosis as well as other

chronic inflammatory diseases, neurodegenerative disorders, and cancer. Further

investigation is required to assess the role of TG2 SUMOylation in oxidative stressdriven pathology of other diseases.


ROS-Responsive Cellular Factors Associated With

Regulation of TG2 Enzymatic Activity

14.5.1 Intracellular Calcium Ion Concentration ([Ca2+]i)

Calcium is a cofactor required for the transamidation activity of TG2, and thus for

TG2 activation. In several reports, the EC50 of calcium for activation of endogenous

or purified recombinant TG2 was estimated to be approximately 100–500 μM

(Begg et al. 2006b; Bergamini and Signorini 1993; Kanchan et al. 2013; Lorand

and Conrad 1984; Signorini et al. 1988). Under physiological conditions, cells

maintain low levels of free calcium ion in the cytosol ([Ca2+]i ¼ ~100 nM)

(Roderick and Cook 2008) and high levels of GTP, an intracellular inhibitor for

transamidation activity of TG2 (Begg et al. 2006b). This indicates that intracellular

TG2 is not active (Shin et al. 2004; Siegel et al. 2008; Zhang et al. 1998) and the

increase of [Ca2+]i is a prerequisite for intracellular TG2 activation.

ROS are known to increase [Ca2+]i via activation of various signaling pathways

and redox-sensitive calcium channels (Bogeski et al. 2011). Indeed, oxidative

stresses elevated the level of [Ca2+]i and calcium chelating agents such as


E.M. Jeong and I.-G. Kim

Fig. 14.5 Cellular mediators regulate ROS-dependent TG2 activation. (1) [Ca2+]i; TG2 is activated by ROS-induced increase of [Ca2+]i (Jeong et al. 2009; Shin et al. 2008). (2) TGFβ; ROS

increase the active form of TGFβ (Barcellos-Hoff and Dix 1996), which activates TG2 via

SMAD3/4-dependent gene(s) expression (Shin et al. 2008). (3) RPL7a and RPL13; it has been

recently suggested that RPL7a and RPL13 are endogenous TG2 inhibitor proteins (Kim 2014).

They interact with TG2, leading to inactivation. ROS promote dissociation of TG2 from the

ribosomal proteins, resulting in TG2 activation. ROS reactive oxygen species, [Ca2+]i intracellular

calcium concentration

BAPTA-AM and EGTA blocked ROS-induced TG2 activation (Fig. 14.5) (Jang

et al. 2010; Jeong et al. 2009; Shin et al. 2008). This demonstrates that ROS activate

TG2 through an increase of [Ca2+]i. However, it is still unknown which redox

signaling pathway(s) and calcium channel(s) are responsible for the increase of

[Ca2+]i to activate TG2 under oxidative stress conditions. Since evidence on the

involvement of [Ca2+]i dysregulation in the pathogenesis of oxidative stress-related

diseases has been accumulating (Hetz and Mollereau 2014; LaFerla 2002; Roderick

and Cook 2008), it is expected that the verification of these [Ca2+]i regulatory

mechanisms will increase our understanding of TG2-related diseases.

14.5.2 TGFβ-Signaling Pathway

ROS oxidize the latent form of TGFβ into active TGFβ (Barcellos-Hoff and Dix

1996), which triggers TG2 activation (Fig. 14.5). In human lens epithelial cells and

ex vivo cultured rodent lens, H2O2 or selenite activates TG2 in a TGFβ-dependent

manner, which catalyzes the aggregation of crystallin proteins and leads to cataract

formation (Shin et al. 2008). Bleomycin induces lung epithelial cells to produce

active TGFβ, which promotes the accumulation of extracellular matrix (ECM) in

lung fibroblasts, resulting in pulmonary fibrosis (Oh et al. 2011). Under these

conditions, intracellular TG2 is activated by an unknown protein; this protein is

upregulated by SMAD3/4 without a change in TG2 expression level (Shin

et al. 2008) (Fig 14.5). Thus, we need to identify the TGFβ-dependent TG2

activator to elucidate the pathogenesis of TG2-mediated inflammation and fibrosis.


Regulation of Transglutaminase 2 by Oxidative Stress


14.5.3 Ribosomal Proteins

Recently, ribosomal proteins, L7a (RPL7a) and L13 (RPL13) have been proposed

to be endogenous TG2 inhibitors (Kim 2014). These ribosomal proteins specifically

inhibit the transamidation activity of TG2, but not of other TG isotypes including

Factor XIIIa, TG1, TG3, and TG4. The inhibitor proteins suppressed TG2 activity

through direct interaction with β-barrel2 domain in TG2 in a mixed inhibition

manner. Thus, intracellular TG2 activity was largely dependent on the expression

levels of the ribosomal proteins. Intriguingly, under oxidative stress conditions, not

only did the interaction between TG2 and inhibitor proteins decrease via increased

[Ca2+]i but also expression levels of the inhibitors decreased via ROS-mediated

suppression of their promoter activity; this resulted in intracellular TG2 activation.

These results suggest that RPL7a and RPL13, along with endogenous small molecule inhibitors for TG2 like GTP, cysteamine, and cystamine may participate in

the prevention of aberrant TG2 activation under physiological conditions.


Concluding Remarks

ROS were thought to be essentially toxic to the cells as they cause oxidative

damage to cellular components. However, a growing body of evidence suggests

that ROS are involved in the regulation of many cellular processes including

proliferation, differentiation, inflammation, survival, and autophagy, by eliciting

redox signaling pathways (Holmstrom and Finkel 2014). The findings presented in

this chapter strongly suggest that TG2 may play a role as a mediator or downstream

effector in redox signaling pathways. At physiological levels of ROS, TG2 helps in

the adaptation to oxidative environments. However, when cells are exposed to high

levels of ROS or persistent oxidative stress, TG2 may contribute to the development of cancer, chronic inflammatory and degenerative diseases.

Interestingly, most TG2 associated disorders are age-related degenerative diseases, in which pathogenesis is closely linked to oxidative stress (Balaban

et al. 2005; Finkel and Holbrook 2000; Iismaa et al. 2009) (Fig. 14.2 and

Table 14.1). Moreover, TG2 is upregulated in the aging process (Lavie and

Weinreb 1996; Park et al. 1999), implying that TG2 may be a key factor in

age-related degenerative diseases even though the exact mechanism of TG2 activation by ROS needs to be clarified.

In conclusion, elucidation of the links between oxidative stress and TG2 will aid

understanding of the pathophysiology of TG2-related diseases and development of

effective therapeutic strategies.


E.M. Jeong and I.-G. Kim


AbdAlla S, Lother H, el Missiry A, Langer A, Sergeev P, el Faramawy Y, Quitterer U (2009)

Angiotensin II AT2 receptor oligomers mediate G-protein dysfunction in an animal model of

Alzheimer disease. J Biol Chem 284:6554–6565

Ai L, Skehan RR, Saydi J, Lin T, Brown KD (2012) Ataxia-Telangiectasia, Mutated (ATM)/

Nuclear factor kappa light chain enhancer of activated B cells (NFkappaB) signaling controls

basal and DNA damage-induced transglutaminase 2 expression. J Biol Chem


Balaban RS, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and aging. Cell 120:483–495

Banerjee R (2012) Redox outside the box: linking extracellular redox remodeling with intracellular redox metabolism. J Biol Chem 287:4397–4402

Barcellos-Hoff MH, Dix TA (1996) Redox-mediated activation of latent transforming growth

factor-beta 1. Mol Endocrinol 10:1077–1083

Basso M, Ratan RR (2013) Transglutaminase is a therapeutic target for oxidative stress,

excitotoxicity and stroke: a new epigenetic kid on the CNS block. J Cereb Blood Flow

Metab 33:809–818

Basso M, Berlin J, Xia L, Sleiman SF, Ko B, Haskew-Layton R, Kim E, Antonyak MA, Cerione

RA, Iismaa SE et al (2012) Transglutaminase inhibition protects against oxidative stressinduced neuronal death downstream of pathological ERK activation. J Neurosci Off J Soc

Neurosci 32:6561–6569

Battaglia G, Farrace MG, Mastroberardino PG, Viti I, Fimia GM, Van Beeumen J, Devreese B,

Melino G, Molinaro G, Busceti CL et al (2007) Transglutaminase 2 ablation leads to defective

function of mitochondrial respiratory complex I affecting neuronal vulnerability in experimental models of extrapyramidal disorders. J Neurochem 100:36–49

Begg GE, Carrington L, Stokes PH, Matthews JM, Wouters MA, Husain A, Lorand L, Iismaa SE,

Graham RM (2006a) Mechanism of allosteric regulation of transglutaminase 2 by GTP. Proc

Natl Acad Sci U S A 103:19683–19688

Begg GE, Holman SR, Stokes PH, Matthews JM, Graham RM, Iismaa SE (2006b) Mutation of a

critical arginine in the GTP-binding site of transglutaminase 2 disinhibits intracellular crosslinking activity. J Biol Chem 281:12603–12609

Bergamini CM, Signorini M (1993) Studies on tissue transglutaminases: interaction of erythrocyte

type-2 transglutaminase with GTP. Biochem J 291(Pt 1):37–39

Bhatt MP, Lim YC, Hwang J, Na S, Kim YM, Ha KS (2013) C-peptide prevents hyperglycemiainduced endothelial apoptosis through inhibition of reactive oxygen species-mediated transglutaminase 2 activation. Diabetes 62:243–253

Bogeski I, Kappl R, Kummerow C, Gulaboski R, Hoth M, Niemeyer BA (2011) Redox regulation

of calcium ion channels: chemical and physiological aspects. Cell Calcium 50:407–423

Cao L, Petrusca DN, Satpathy M, Nakshatri H, Petrache I, Matei D (2008) Tissue transglutaminase

protects epithelial ovarian cancer cells from cisplatin-induced apoptosis by promoting cell

survival signaling. Carcinogenesis 29:1893–1900

Chung SI, Folk JE (1970) Mechanism of the inactivation of guinea pig liver transglutaminase by

tetrathionate. J Biol Chem 245:681–689

Connellan JM, Folk JE (1969) Mechanism of the inactivation of guinea pig liver transglutaminase

by 5,50 -dithiobis-(2-nitrobenzoic acid). J Biol Chem 244:3173–3181

Cutting GR (2015) Cystic fibrosis genetics: from molecular understanding to clinical application.

Nat Rev Genet 16:45–56

D’Autreaux B, Toledano MB (2007) ROS as signalling molecules: mechanisms that generate

specificity in ROS homeostasis. Nat Rev Mol Cell Biol 8:813–824

De Laurenzi V, Melino G (2001) Gene disruption of tissue transglutaminase. Mol Cell Biol


Falasca L, Farrace MG, Rinaldi A, Tuosto L, Melino G, Piacentini M (2008) Transglutaminase

type II is involved in the pathogenesis of endotoxic shock. J Immunol 180:2616–2624


Regulation of Transglutaminase 2 by Oxidative Stress


Fesus L, Tarcsa E (1989) Formation of N epsilon-(gamma-glutamyl)-lysine isodipeptide in

Chinese-hamster ovary cells. Biochem J 263:843–848

Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature


Geiss-Friedlander R, Melchior F (2007) Concepts in sumoylation: a decade on. Nat Rev Mol Cell

Biol 8:947–956

Green J, Paget MS (2004) Bacterial redox sensors. Nat Rev Microbiol 2:954–966

Grek CL, Zhang J, Manevich Y, Townsend DM, Tew KD (2013) Causes and consequences of

cysteine S-glutathionylation. J Biol Chem 288:26497–26504

Han BG, Cho JW, Cho YD, Jeong KC, Kim SY, Lee BI (2010) Crystal structure of human

transglutaminase 2 in complex with adenosine triphosphate. Int J Biol Macromol 47:190–195

Herman JF, Mangala LS, Mehta K (2006) Implications of increased tissue transglutaminase (TG2)

expression in drug-resistant breast cancer (MCF-7) cells. Oncogene 25:3049–3058

Hetz C, Mollereau B (2014) Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat Rev Neurosci 15:233–249

Holmstrom KM, Finkel T (2014) Cellular mechanisms and physiological consequences of redoxdependent signalling. Nat Rev Mol Cell Biol 15:411–421

Hybertson BM, Gao B, Bose SK, McCord JM (2011) Oxidative stress in health and disease: the

therapeutic potential of Nrf2 activation. Mol Asp Med 32:234–246

Iismaa SE, Mearns BM, Lorand L, Graham RM (2009) Transglutaminases and disease: lessons

from genetically engineered mouse models and inherited disorders. Physiol Rev 89:991–1023

Jandu SK, Webb AK, Pak A, Sevinc B, Nyhan D, Belkin AM, Flavahan NA, Berkowitz DE,

Santhanam L (2013) Nitric oxide regulates tissue transglutaminase localization and function in

the vasculature. Amino Acids 44:261–269

Jang GY, Jeon JH, Cho SY, Shin DM, Kim CW, Jeong EM, Bae HC, Kim TW, Lee SH, Choi Y

et al (2010) Transglutaminase 2 suppresses apoptosis by modulating caspase 3 and NF-kappaB

activity in hypoxic tumor cells. Oncogene 29:356–367

Jang TH, Lee DS, Choi K, Jeong EM, Kim IG, Kim YW, Chun JN, Jeon JH, Park HH (2014)

Crystal structure of transglutaminase 2 with GTP complex and amino acid sequence evidence

of evolution of GTP binding site. PLoS ONE 9:e107005

Jeong EM, Kim CW, Cho SY, Jang GY, Shin DM, Jeon JH, Kim IG (2009) Degradation of

transglutaminase 2 by calcium-mediated ubiquitination responding to high oxidative stress.

FEBS Lett 583:648–654

Jin X, Stamnaes J, Klock C, DiRaimondo TR, Sollid LM, Khosla C (2011) Activation of

extracellular transglutaminase 2 by thioredoxin. J Biol Chem 286:37866–37873

Kanchan K, Ergulen E, Kiraly R, Simon-Vecsei Z, Fuxreiter M, Fesus L (2013) Identification of a

specific one amino acid change in recombinant human transglutaminase 2 that regulates its

activity and calcium sensitivity. Biochem J 455:261–272

Kim SY (2006) Transglutaminase 2 in inflammation. Front Biosci 11:3026–3035

Kim IG (2014) The mechanism of oxidative stress induced transglutaminase 2 activation. Oral

presentation at Transglutaminases in human disease processes gordon research conference,

Lucca, 29 June–4 July 2014

Kuncio GS, Tsyganskaya M, Zhu J, Liu SL, Nagy L, Thomazy V, Davies PJ, Zern MA (1998)

TNF-alpha modulates expression of the tissue transglutaminase gene in liver cells. Am J

Physiol 274:G240–G245

LaFerla FM (2002) Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease.

Nat Rev Neurosci 3:862–872

Lai TS, Hausladen A, Slaughter TF, Eu JP, Stamler JS, Greenberg CS (2001) Calcium regulates

S-nitrosylation, denitrosylation, and activity of tissue transglutaminase. Biochemistry


Lai TS, Tucker T, Burke JR, Strittmatter WJ, Greenberg CS (2004) Effect of tissue transglutaminase on the solubility of proteins containing expanded polyglutamine repeats.

J Neurochem 88:1253–1260


E.M. Jeong and I.-G. Kim

Lavie L, Weinreb O (1996) Age- and strain-related changes in tissue transglutaminase activity in

murine macrophages: the effects of inflammation and induction by retinol. Mech Ageing Dev


Lee J, Kim YS, Choi DH, Bang MS, Han TR, Joh TH, Kim SY (2004) Transglutaminase 2 induces

nuclear factor-kappaB activation via a novel pathway in BV-2 microglia. J Biol Chem


Lee SM, Jeong EM, Jeong J, Shin DM, Lee HJ, Kim HJ, Lim J, Lee JH, Cho SY, Kim MK

et al (2012) Cysteamine prevents the development of lens opacity in a rat model of seleniteinduced cataract. Invest Ophthalmol Vis Sci 53:1452–1459

Liu S, Cerione RA, Clardy J (2002) Structural basis for the guanine nucleotide-binding activity of

tissue transglutaminase and its regulation of transamidation activity. Proc Natl Acad Sci U S A


Lorand L, Conrad SM (1984) Transglutaminases. Mol Cell Biochem 58:9–35

Luciani A, Villella VR, Vasaturo A, Giardino I, Raia V, Pettoello-Mantovani M, D’Apolito M,

Guido S, Leal T, Quaratino S et al (2009) SUMOylation of tissue transglutaminase as link

between oxidative stress and inflammation. J Immunol 183:2775–2784

Luciani A, Villella VR, Esposito S, Brunetti-Pierri N, Medina D, Settembre C, Gavina M, Pulze L,

Giardino I, Pettoello-Mantovani M et al (2010a) Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. Nat

Cell Biol 12:863–875

Luciani A, Villella VR, Vasaturo A, Giardino I, Pettoello-Mantovani M, Guido S, Cexus ON,

Peake N, Londei M, Quaratino S et al (2010b) Lysosomal accumulation of gliadin p31-43

peptide induces oxidative stress and tissue transglutaminase-mediated PPARgamma

downregulation in intestinal epithelial cells and coeliac mucosa. Gut 59:311–319

Maiuri L, Luciani A, Giardino I, Raia V, Villella VR, D’Apolito M, Pettoello-Mantovani M,

Guido S, Ciacci C, Cimmino M et al (2008) Tissue transglutaminase activation modulates

inflammation in cystic fibrosis via PPARgamma down-regulation. J Immunol 180:7697–7705

Marino G, Niso-Santano M, Baehrecke EH, Kroemer G (2014) Self-consumption: the interplay of

autophagy and apoptosis. Nat Rev Mol Cell Biol 15:81–94

Mayne ST (2003) Antioxidant nutrients and chronic disease: use of biomarkers of exposure and

oxidative stress status in epidemiologic research. J Nutr 133(Suppl 3):933S–940S

Mehta K (1994) High levels of transglutaminase expression in doxorubicin-resistant human breast

carcinoma cells. Int J Cancer J Int du Cancer 58:400–406

Monteith GR, McAndrew D, Faddy HM, Roberts-Thomson SJ (2007) Calcium and cancer:

targeting Ca2+ transport. Nat Rev Cancer 7:519–530

Nathan C, Cunningham-Bussel A (2013) Beyond oxidative stress: an immunologist’s guide to

reactive oxygen species. Nat Rev Immunol 13:349–361

Oh K, Park HB, Byoun OJ, Shin DM, Jeong EM, Kim YW, Kim YS, Melino G, Kim IG, Lee DS

(2011) Epithelial transglutaminase 2 is needed for T cell interleukin-17 production and

subsequent pulmonary inflammation and fibrosis in bleomycin-treated mice. J Exp Med


Park SC, Yeo EJ, Han JA, Hwang YC, Choi JY, Park JS, Park YH, Kim KO, Kim IG, Seong SC

et al (1999) Aging process is accompanied by increase of transglutaminase C. J Gerontol A:

Biol Med Sci 54:B78–B83

Penumatsa KC, Toksoz D, Warburton RR, Hilmer AJ, Liu T, Khosla C, Comhair SA, Fanburg BL

(2014) Role of hypoxia-induced transglutaminase 2 in pulmonary artery smooth muscle cell

proliferation. Am J Physiol Lung Cell Mol Physiol 307:L576–L585

Perkins ND (2007) Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat

Rev Mol Cell Biol 8:49–62

Perkins ND, Gilmore TD (2006) Good cop, bad cop: the different faces of NF-kappaB. Cell Death

Differ 13:759–772

Pinkas DM, Strop P, Brunger AT, Khosla C (2007) Transglutaminase 2 undergoes a large

conformational change upon activation. PLoS Biol 5:e327


Regulation of Transglutaminase 2 by Oxidative Stress


Roderick HL, Cook SJ (2008) Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer

cell proliferation and survival. Nat Rev Cancer 8:361–375

Sabharwal SS, Schumacker PT (2014) Mitochondrial ROS in cancer: initiators, amplifiers or an

Achilles’ heel? Nat Rev Cancer 14:709–721

Santhanam L, Tuday EC, Webb AK, Dowzicky P, Kim JH, Oh YJ, Sikka G, Kuo M, Halushka

MK, Macgregor AM et al (2010) Decreased S-nitrosylation of tissue transglutaminase contributes to age-related increases in vascular stiffness. Circ Res 107:117–125

Santhanam L, Berkowitz DE, Belkin AM (2011) Nitric oxide regulates non-classical secretion of

tissue transglutaminase. Commun Integr Biol 4:584–586

Sarkar DD, Edwards SK, Mauser JA, Suarez AM, Serowoky MA, Hudok NL, Hudok PL,

Nunez M, Weber CS, Lynch RM et al (2013) Increased redox-sensitive green fluorescent

protein reduction potential in the endoplasmic reticulum following glutathione-mediated

dimerization. Biochemistry 52:3332–3345

Schofield CJ, Ratcliffe PJ (2004) Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol


Segers-Nolten IM, Wilhelmus MM, Veldhuis G, van Rooijen BD, Drukarch B, Subramaniam V

(2008) Tissue transglutaminase modulates alpha-synuclein oligomerization. Protein Sci Publ

Protein Soc 17:1395–1402

Shin DM, Jeon JH, Kim CW, Cho SY, Kwon JC, Lee HJ, Choi KH, Park SC, Kim IG (2004) Cell

type-specific activation of intracellular transglutaminase 2 by oxidative stress or ultraviolet

irradiation: implications of transglutaminase 2 in age-related cataractogenesis. J Biol Chem


Shin DM, Jeon JH, Kim CW, Cho SY, Lee HJ, Jang GY, Jeong EM, Lee DS, Kang JH, Melino G

et al (2008) TGFbeta mediates activation of transglutaminase 2 in response to oxidative stress

that leads to protein aggregation. Faseb J Off Publ Fed Am Soc Exp Biol 22:2498–2507

Siegel M, Strnad P, Watts RE, Choi K, Jabri B, Omary MB, Khosla C (2008) Extracellular

transglutaminase 2 is catalytically inactive, but is transiently activated upon tissue injury.

PLoS ONE 3:e1861

Signorini M, Bortolotti F, Poltronieri L, Bergamini CM (1988) Human erythrocyte transglutaminase: purification and preliminary characterisation. Biol Chem Hoppe Seyler 369:275–281

Stamnaes J, Pinkas DM, Fleckenstein B, Khosla C, Sollid LM (2010) Redox regulation of

transglutaminase 2 activity. J Biol Chem 285:25402–25409

Steinhubl SR (2008) Why have antioxidants failed in clinical trials? Am J Cardiol 101:14D–19D

Suto N, Ikura K, Sasaki R (1993) Expression induced by interleukin-6 of tissue-type transglutaminase in human hepatoblastoma HepG2 cells. J Biol Chem 268:7469–7473

Telci D, Collighan RJ, Basaga H, Griffin M (2009) Increased TG2 expression can result in

induction of transforming growth factor beta1, causing increased synthesis and deposition of

matrix proteins, which can be regulated by nitric oxide. J Biol Chem 284:29547–29558

Tucholski J, Roth KA, Johnson GV (2006) Tissue transglutaminase overexpression in the brain

potentiates calcium-induced hippocampal damage. J Neurochem 97:582–594

Verma A, Mehta K (2007) Tissue transglutaminase-mediated chemoresistance in cancer cells.

Drug Resist Updat 10:144–151

Wang Z, Perez M, Caja S, Melino G, Johnson TS, Lindfors K, Griffin M (2013) A novel

extracellular role for tissue transglutaminase in matrix-bound VEGF-mediated angiogenesis.

Cell Death Dis 4:e808

Watson WH, Pohl J, Montfort WR, Stuchlik O, Reed MS, Powis G, Jones DP (2003) Redox

potential of human thioredoxin 1 and identification of a second dithiol/disulfide motif. J Biol

Chem 278:33408–33415

Wu ZH, Shi Y, Tibbetts RS, Miyamoto S (2006) Molecular linkage between the kinase ATM and

NF-kappaB signaling in response to genotoxic stimuli. Science 311:1141–1146

Zhang J, Lesort M, Guttmann RP, Johnson GV (1998) Modulation of the in situ activity of tissue

transglutaminase by calcium and GTP. J Biol Chem 273:2288–2295

Chapter 15

Blood Coagulation Factor XIII: A

Multifunctional Transglutaminase

Moyuru Hayashi and Kohji Kasahara

Abstract Factor XIII is a pro-enzyme of plasma transglutaminase consisting of

two enzymatic A subunits and two non-catalytic B subunits, and platelet transglutaminase consisting of two enzymatic A subunits. FXIII plays a critical role in the

generation of a stable hemostatic plug, wound healing, maintaining pregnancy,

angiogenesis, apoptosis and bacterial immobilization. FXIII catalyzes

intermolecular cross-linking reactions between fibrin monomers and α2antiplasmin. These reactions increase the mechanical strength of the fibrin clot

and its resistance to proteolytic degradation. Congenital FXIII deficiency is a rare

autosomal recessive disorder, most cases of which are caused by defects in the

FXIII-A gene, leading to a bleeding tendency. An autoimmune hemophilia-like

disease is caused by anti-FXIII antibodies. Platelet surface FXIII-A2 is involved in

fibrin translocation to lipid rafts and outside-in signaling, leading to clot retraction.

FXIII-A2-mediated protein cross-linking is associated with assembly of the extracellular matrix on a variety of cell surfaces in physiological events such as


Keywords Factor XIII • Platelets • Surface • Clot retraction • Lipid rafts •




The blood coagulation cascade has evolved as a defense mechanism for

maintaining hemostasis during blood vessel injury. This process is controlled by

a signaling cascade consisting of 13 coagulation factors. There are two separate

pathways, the intrinsic and extrinsic. The intrinsic pathway is activated by trauma

inside the vascular system, and is activated by platelets, exposed endothelium, or

collagen. This pathway involves factors XII, XI, IX, and VIII. The extrinsic

pathway is activated by external trauma that causes blood to escape from the

vascular system. This pathway involves factor VII. These eventually join together

to form the common pathway. The common pathway involves factors I, II, V, and

M. Hayashi • K. Kasahara (*)

Laboratory of Biomembrane, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

e-mail: kasahara-kj@igakuken.or.jp

© Springer Japan 2015

K. Hitomi et al. (eds.), Transglutaminases, DOI 10.1007/978-4-431-55825-5_15


Tài liệu bạn tìm kiếm đã sẵn sàng tải về

4 Post-Translational Modifications (PTMs) of TG2 in Response to Oxidative StressPost-Translational Modifications (PTMs)

Tải bản đầy đủ ngay(0 tr)