Transglutaminase 2 is expressed and active on the surface of human monocyte-derived dendritic cells and macrophages

Hodrea, Judit; Demény, Máté Ágoston; Májai, Gyöngyike; Sarang, Zsolt; Korponay-Szabó, Ilma Rita; Fésüs, László

doi:10.1016/j.imlet.2009.12.010

Cited by 38 publications

(37 citation statements)

References 60 publications

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“…In addition, tTG co-localizes with insulin-containing granules in human beta cells [10], indicating the potential for an increase in tTG activity to result in deamidation of insulin. In DC, levels of cell surface tTG increase during maturation, implying that tTG could be incorporated into endosomes during antigen uptake, thereby bringing tTG into direct contact with antigens during processing [11]. In our hands, DC increased tTG activity during inflammatory maturation.…”

Section: Discussionsupporting

confidence: 48%

“…Conversely, we observed tTG activity in both DC and tolDC in the absence of inflammation; this could be a mechanism for inducing peripheral tolerance to modified autoantigens, whereby native islet autoantigens taken up by immature DC are deamidated and presented in a tolerogenic fashion. tTG is also present in other cells of the myeloid lineage, indicating that infiltrating monocytes and tissue resident macrophages could also contribute to the production of modified islet proteins and immune activation or tolerance induction, depending on the inflammatory context [11].…”

Section: Discussionmentioning

confidence: 99%

“…Currently, the cells capable of deamidating islet autoantigens, as well as the environment contributing to generating deamidated islet autoantigens, are unknown, but there is evidence that both myeloid cells and beta cells express tTG [10,11]. Here, we investigated human dendritic cells (DC) and tolerogenic (tol)DC, as professional antigen-presenting cells capable of priming naive T cells [12][13][14], as well as human pancreatic islets under resting and inflammatory conditions.…”

Section: Introductionmentioning

confidence: 99%

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Human islets and dendritic cells generate post-translationally modified islet autoantigens

McLaughlin

Haan

Zaldumbide³

et al. 2016

Clinical and Experimental Immunology

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SummaryThe initiation of type 1 diabetes (T1D) requires a break in peripheral tolerance. New insights into neoepitope formation indicate that posttranslational modification of islet autoantigens, for example via deamidation, may be an important component of disease initiation or exacerbation. Indeed, deamidation of islet autoantigens increases their binding affinity to the T1D highest-risk human leucocyte antigen (HLA) haplotypes HLA-DR3/DQ2 and -DR4/DQ8, increasing the chance that T cells reactive to deamidated autoantigens can be activated upon T cell receptor ligation. Here we investigated human pancreatic islets and inflammatory and tolerogenic human dendritic cells (DC and tolDC) as potential sources of deamidated islet autoantigens and examined whether deamidation is altered in an inflammatory environment. Islets, DC and tolDC contained tissue transglutaminase, the key enzyme responsible for peptide deamidation, and enzyme activity increased following an inflammatory insult. Islets treated with inflammatory cytokines were found to contain deamidated insulin C-peptide. DC, heterozygous for the T1D highest-risk DQ2/8, pulsed with native islet autoantigens could present naturally processed deamidated neoepitopes. HLA-DQ2 or -DQ8 homozygous DC did not present deamidated islet peptides. This study identifies both human islets and DC as sources of deamidated islet autoantigens and implicates inflammatory activation of tissue transglutaminase as a potential mechanism for islet and DC deamidation.

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Section: Discussionsupporting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human islets and dendritic cells generate post-translationally modified islet autoantigens

McLaughlin

Haan

Zaldumbide³

et al. 2016

Clinical and Experimental Immunology

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“…One of the monoclonal TG2 antibodies, 6B9, was claimed to recognize cell-surface TG2, but later it was determined that it actually recognized CD44 on the cell surface and not TG2 [174]. Recent work from our group showed that in contrast to other commercially available TG2 antibodies, TG100 was the only antibody that recognized cell-surface TG2 on monocyte-derived dendritic cells and macrophages [175], emphasizing the need for testing several antibodies to have a complete overview of the biochemical properties of the enzyme.…”

Section: Antibodies Targeting the Linear Epitope On Tg2mentioning

confidence: 99%

Physiological, pathological, and structural implications of non-enzymatic protein–protein interactions of the multifunctional human transglutaminase 2

Kanchan

Fuxreiter

Fésüs

2015

Cell. Mol. Life Sci.

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Transglutaminase 2 (TG2) is a ubiquitously expressed member of an enzyme family catalyzing Ca(2+)-dependent transamidation of proteins. It is a multifunctional protein having several well-defined enzymatic (GTP binding and hydrolysis, protein disulfide isomerase, and protein kinase activities) and non-enzymatic (multiple interactions in protein scaffolds) functions. Unlike its enzymatic interactions, the significance of TG2's non-enzymatic regulation of its activities has recently gained importance. In this review, we summarize all the partners that directly interact with TG2 in a non-enzymatic manner and analyze how these interactions could modulate the crosslinking activity and cellular functions of TG2 in different cell compartments. We have found that TG2 mostly acts as a scaffold to bridge various proteins, leading to different functional outcomes. We have also studied how specific structural features, such as intrinsically disordered regions and embedded short linear motifs contribute to multifunctionality of TG2. Conformational diversity of intrinsically disordered regions enables them to interact with multiple partners, which can result in different biological outcomes. Indeed, ID regions in TG2 were identified in functionally relevant locations, indicating that they could facilitate conformational transitions towards the catalytically competent form. We reason that these structural features contribute to modulating the physiological and pathological functions of TG2 and could provide a new direction for detecting unique regulatory partners. Additionally, we have assembled all known anti-TG2 antibodies and have discussed their significance as a toolbox for identifying and confirming novel TG2 regulatory functions.

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“…These cells expressed TG2 at the cell surface [39] with the exception of THP-1 parental cells and THP-1/VD3 cells where TG2 was not detectable. Given the monocyte-like (relatively immature) morphology of these cells [28], these data suggest that TG2 expression is linked to monocyte/macrophage maturity [40,41].…”

Section: Discussionmentioning

confidence: 98%

Transglutaminase 2 interacts with syndecan-4 and CD44 at the surface of human macrophages to promote removal of apoptotic cells

Nadella

Wang

Johnson

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Tissue transglutaminase (TG2) is a multifunctional protein cross-linking enzyme that has been implicated in apoptotic cell clearance but is also important in many other cell functions including cell adhesion, migration and monocyte to macrophage differentiation. Cell surface-associated TG2 regulates cell adhesion and migration, via its association with receptors such as syndecan-4 and β1 and β3 integrins. Whilst defective apoptotic cell clearance has been described in TG2-deficient mice, the precise role of TG2 in apoptotic cell clearance remains ill-defined. Our work addresses the role of macrophage extracellular TG2 in apoptotic cell corpse clearance. Here we reveal TG2 expression and activity (cytosolic and cell surface) in human macrophages and demonstrate that inhibitors of protein crosslinking activity reduce macrophage clearance of dying cells. We show also that cell-impermeable TG2 inhibitors significantly inhibit the ability of macrophages to migrate and clear apoptotic cells through reduced macrophage recruitment to, and binding of, apoptotic cells. Association studies reveal TG2-syndecan-4 interaction through heparan sulphate side chains, and knockdown of syndecan-4 reduces cell surface TG2 activity and apoptotic cell clearance. Furthermore, inhibition of TG2 activity reduces crosslinking of CD44, reported to augment AC clearance. Thus our data define a role for TG2 activity at the surface of human macrophages in multiple stages of AC clearance and we propose that TG2, in association with heparan sulphates, may exert its effect on AC clearance via a mechanism involving the crosslinking of CD44.

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Transglutaminase 2 is expressed and active on the surface of human monocyte-derived dendritic cells and macrophages

Cited by 38 publications

References 60 publications

Human islets and dendritic cells generate post-translationally modified islet autoantigens

Human islets and dendritic cells generate post-translationally modified islet autoantigens

Physiological, pathological, and structural implications of non-enzymatic protein–protein interactions of the multifunctional human transglutaminase 2

Transglutaminase 2 interacts with syndecan-4 and CD44 at the surface of human macrophages to promote removal of apoptotic cells

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