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

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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



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323



(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



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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

identified.



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



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325



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.



14.5



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



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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.



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327



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.



14.6



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.



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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

differentiation.

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

Transamidation



15.1



Introduction



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



333



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