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Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 22312

Special Issue Editors

Prof. Dr. Simone Beninati

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Guest Editor
Department of Biology, University of Tor Vergata, Rome, Italy
Interests: experimental oncology; biochemistry
Special Issues, Collections and Topics in MDPI journals
Dr. Carlo Mischiati

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Guest Editor
Clinical Biochemistry Laboratory, Department of Neurosciences and Rehabilitation, Faculty of Medicine, Pharmacy and Prevention, University of Ferrara, Via Luigi Borsari 46, Ferrara, Italy
Interests: biochemistry; molecular biology; medical genetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the second volume of our previous Special Issue "Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications". Transglutaminases are ubiquitous enzymes which catalyze posttranslational modifications of proteins. Recently, transglutaminase-catalyzed posttranslational modification of proteins has been shown to be involved in the molecular mechanisms responsible for human diseases. This family of enzymes has been associated with inflammation, cancer, fibrosis, cardiovascular disease, and celiac disease, in which it plays either a protective role or contributes to the pathogenesis. Transglutaminase activity has been hypothesized to also be involved in the pathogenetic mechanisms responsible for several human neurodegenerative diseases. Alzheimer’s disease and other neurodegenerative diseases, such as Parkinson’s disease, supranuclear palsy, Huntington’s disease, and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains.

We are pleased to invite you to contribute to the Special Issue, “Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications 2.0", which will be published in the International Journal of Molecular Sciences (IF 4.556), an international peer-reviewed open access journal providing an advanced forum for biochemistry, molecular and cell biology, and molecular biophysics, published semi-monthly online by MDPI. Citations are available in PubMed, and full texts are archived in PubMed Central. The objective of this Special Issue is to collect and publish both experimental and theoretical contributions from original and high-quality research articles and to encourage researchers to investigate topics in the field of transglutaminases in various diseases.

Prof. Dr. Simone Beninati
Dr. Carlo Mischiati
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Published Papers (7 papers)

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Research

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12 pages, 2301 KiB  
Article
A Central Contribution of TG2 Activity to the Antiproliferative and Pro-Apoptotic Effects of Caffeic Acid in K562 Cells of Human Chronic Myeloid Leukemia
by Giordana Feriotto, Federico Tagliati, Arianna Brunello, Simone Beninati, Claudio Tabolacci and Carlo Mischiati
Int. J. Mol. Sci. 2022, 23(23), 15004; https://doi.org/10.3390/ijms232315004 - 30 Nov 2022
Cited by 3 | Viewed by 1704
Abstract
Caffeic acid (CA) has shown antitumor activity in numerous solid and blood cancers. We have recently reported that CA is active in reducing proliferation and triggering apoptosis in both Imatinib-sensitive and resistant Chronic Myeloid Leukemia (CML) cells. Tissue transglutaminase type 2 (TG2) enzyme [...] Read more.
Caffeic acid (CA) has shown antitumor activity in numerous solid and blood cancers. We have recently reported that CA is active in reducing proliferation and triggering apoptosis in both Imatinib-sensitive and resistant Chronic Myeloid Leukemia (CML) cells. Tissue transglutaminase type 2 (TG2) enzyme is involved in cell proliferation and apoptosis of numerous types of cancer. However, its activity has different effects depending on the type of tumor. This work investigated the possible involvement of TG2 activation in the triggering of CA-dependent anticancer effects on the K562 cell line, which was studied as a model of CML. CA-dependent changes in TG2 activity were compared with the effects on cell proliferation and apoptosis. The use of N-acetylcysteine (NAC), an antioxidant molecule, suggested that the antiproliferative effect of CA was due to the increase in reactive oxygen species (ROS). The use of a TG2 inhibitor showed that TG2 activity was responsible for the increase in ROS generated by CA and reduced both caspase activation and triggering of CA-dependent apoptosis. The knocking-down of TGM2 transcripts confirmed the crucial involvement of TG2 activation in CML cell death. In conclusion, the data reported, in addition to ascertaining the important role of TG2 activation in the antiproliferative and pro-apoptotic mechanism of CA allowed us to hypothesize a possible therapeutic utility of the molecules capable of triggering the activation pathways of TG2 in the treatment of CML. Full article
(This article belongs to the Special Issue Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications 2.0)
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32 pages, 5434 KiB  
Article
Application of a Fluorescence Anisotropy-Based Assay to Quantify Transglutaminase 2 Activity in Cell Lysates
by Sandra Hauser, Paul Sommerfeld, Johanna Wodtke, Christoph Hauser, Paul Schlitterlau, Jens Pietzsch, Reik Löser, Markus Pietsch and Robert Wodtke
Int. J. Mol. Sci. 2022, 23(9), 4475; https://doi.org/10.3390/ijms23094475 - 19 Apr 2022
Cited by 2 | Viewed by 2774
Abstract
Transglutaminase 2 (TGase 2) is a multifunctional protein which is involved in various physiological and pathophysiological processes. The latter also include its participation in the development and progression of malignant neoplasms, which are often accompanied by increased protein synthesis. In addition to the [...] Read more.
Transglutaminase 2 (TGase 2) is a multifunctional protein which is involved in various physiological and pathophysiological processes. The latter also include its participation in the development and progression of malignant neoplasms, which are often accompanied by increased protein synthesis. In addition to the elucidation of the molecular functions of TGase 2 in tumor cells, knowledge of its concentration that is available for targeting by theranostic agents is a valuable information. Herein, we describe the application of a recently developed fluorescence anisotropy (FA)-based assay for the quantitative expression profiling of TGase 2 by means of transamidase-active enzyme in cell lysates. This assay is based on the incorporation of rhodamine B-isonipecotyl-cadaverine (R-I-Cad) into N,N-dimethylated casein (DMC), which results in an increase in the FA signal over time. It was shown that this reaction is not only catalyzed by TGase 2 but also by TGases 1, 3, and 6 and factor XIIIa using recombinant proteins. Therefore, control measurements in the presence of a selective irreversible TGase 2 inhibitor were mandatory to ascertain the specific contribution of TGase 2 to the overall FA rate. To validate the assay regarding the quality of quantification, spike/recovery and linearity of dilution experiments were performed. A total of 25 cancer and 5 noncancer cell lines were characterized with this assay method in terms of their activatable TGase 2 concentration (fmol/µg protein lysate) and the results were compared to protein synthesis data obtained by Western blotting. Moreover, complementary protein quantification methods using a biotinylated irreversible TGase 2 inhibitor as an activity-based probe and a commercially available ELISA were applied to selected cell lines to further validate the results obtained by the FA-based assay. Overall, the present study demonstrates that the FA-based assay using the substrate pair R-I-Cad and DMC represents a facile, homogenous and continuous method for quantifying TGase 2 activity in cell lysates. Full article
(This article belongs to the Special Issue Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications 2.0)
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15 pages, 2802 KiB  
Article
Double-Stranded RNA Enhances Matrix Metalloproteinase-1 and -13 Expressions through TLR3-Dependent Activation of Transglutaminase 2 in Dermal Fibroblasts
by Ah-Young Hong, Seok-Jin Lee, Ki Baek Lee, Ji-Woong Shin, Eui Man Jeong and In-Gyu Kim
Int. J. Mol. Sci. 2022, 23(5), 2709; https://doi.org/10.3390/ijms23052709 - 28 Feb 2022
Cited by 2 | Viewed by 2043
Abstract
UV-irradiation induces the secretion of double-stranded RNA (dsRNA) derived from damaged noncoding RNAs in keratinocytes, which enhance the expression of matrix metalloproteinases (MMP) in non-irradiated dermal fibroblasts, leading to dysregulation of extracellular matrix homeostasis. However, the signaling pathway responsible for dsRNA-induced MMP expression [...] Read more.
UV-irradiation induces the secretion of double-stranded RNA (dsRNA) derived from damaged noncoding RNAs in keratinocytes, which enhance the expression of matrix metalloproteinases (MMP) in non-irradiated dermal fibroblasts, leading to dysregulation of extracellular matrix homeostasis. However, the signaling pathway responsible for dsRNA-induced MMP expression has not been fully understood. Transglutaminase 2 (TG2) is an enzyme that modifies substrate proteins by incorporating polyamine or crosslinking of proteins, thereby regulating their functions. In this study, we showed that TG2 mediates dsRNA-induced MMP-1 expression through NF-κB activation. Treatment of poly(I:C), a synthetic dsRNA analogue binding to toll-like receptor 3 (TLR3), generates ROS, which in turn activates TG2 in dermal fibroblast. Subsequently, TG2 activity enhances translocation of p65 into the nucleus, where it augments transcription of MMP. We confirmed these results by assessing the level of MMP expression in Tlr3−/−, TG2-knockdowned and Tgm2−/− dermal fibroblasts after poly(I:C)-treatment. Moreover, treatment with quercetin showed dose-dependent suppression of poly(I:C)-induced MMP expression. Furthermore, ex vivo cultured skin from Tgm2−/− mice exhibited a significantly reduced level of MMP mRNA compared with those from wild-type mice. Our results indicate that TG2 is a critical regulator in dsRNA-induced MMP expression, providing a new target and molecular basis for antioxidant therapy in preventing collagen degradation. Full article
(This article belongs to the Special Issue Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications 2.0)
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15 pages, 16542 KiB  
Article
Changes in Non-Deamidated versus Deamidated Epitope Targeting and Disease Prediction during the Antibody Response to Gliadin and Transglutaminase of Infants at Risk for Celiac Disease
by Ádám Diós, Bharani Srinivasan, Judit Gyimesi, Katharina Werkstetter, Rudolf Valenta, Sibylle Koletzko and Ilma R. Korponay-Szabó
Int. J. Mol. Sci. 2022, 23(5), 2498; https://doi.org/10.3390/ijms23052498 - 24 Feb 2022
Cited by 1 | Viewed by 2484
Abstract
Celiac disease (CeD) is a conditional autoimmune disorder with T cell-mediated immune response to gluten coupled with antibody production to gliadin and the self-protein tissue transglutaminase (TG2). TG2 contributes to the CeD pathomechanism by deamidating gliadin, thereby generating more immunogenic peptides. Anti-gliadin antibodies [...] Read more.
Celiac disease (CeD) is a conditional autoimmune disorder with T cell-mediated immune response to gluten coupled with antibody production to gliadin and the self-protein tissue transglutaminase (TG2). TG2 contributes to the CeD pathomechanism by deamidating gliadin, thereby generating more immunogenic peptides. Anti-gliadin antibodies may appear before the autoantibody production. The scope of this study was to dissect these early antibody responses by investigating serum samples collected during the PreventCD prospective double-blind study, where infants with high CeD risk were randomized to 200 mg daily gluten intake or placebo from 4 to 6 months of age, followed by frequent blood testing on regular gluten consumption in both groups. After primary gluten intake, children with or without later CeD produced IgA and IgG antibodies which preferentially recognized non-deamidated gliadin peptides. At CeD development with anti-TG2 seroconversion, there was a significant increase in the antibody reaction toward deamidated gliadin peptides (DGP), with maturation in the binding strength for the PEQPFP gamma-gliadin core peptide. The earliest produced autoantibodies targeted TG2’s celiac epitope 2. Our results reveal a qualitative change in the gliadin-directed humoral immune response at the time when anti-TG2 antibodies appear, but anti-DGP antibodies in the absence of anti-TG2 antibodies are not disease-predictive. Full article
(This article belongs to the Special Issue Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications 2.0)
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Review

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11 pages, 1152 KiB  
Review
Antibody Responses to Transglutaminase 3 in Dermatitis Herpetiformis: Lessons from Celiac Disease
by Helka Kaunisto, Teea Salmi, Katri Lindfors and Esko Kemppainen
Int. J. Mol. Sci. 2022, 23(6), 2910; https://doi.org/10.3390/ijms23062910 - 8 Mar 2022
Cited by 10 | Viewed by 3168
Abstract
Dermatitis herpetiformis (DH) is the skin manifestation of celiac disease, presenting with a blistering rash typically on the knees, elbows, buttocks and scalp. In both DH and celiac disease, exposure to dietary gluten triggers a cascade of events resulting in the production of [...] Read more.
Dermatitis herpetiformis (DH) is the skin manifestation of celiac disease, presenting with a blistering rash typically on the knees, elbows, buttocks and scalp. In both DH and celiac disease, exposure to dietary gluten triggers a cascade of events resulting in the production of autoantibodies against the transglutaminase (TG) enzyme, mainly TG2 but often also TG3. The latter is considered to be the primary autoantigen in DH. The dynamics of the development of the TG2-targeted autoimmune response have been studied in depth in celiac disease, but the immunological process underlying DH pathophysiology is incompletely understood. Part of this process is the occurrence of granular deposits of IgA and TG3 in the perilesional skin. While this serves as the primary diagnostic finding in DH, the role of these immunocomplexes in the pathogenesis is unknown. Intriguingly, even though gluten-intolerance likely develops initially in a similar manner in both DH and celiac disease, after the onset of the disease, its manifestations differ widely. Full article
(This article belongs to the Special Issue Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications 2.0)
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17 pages, 829 KiB  
Review
Current Strategies for the Gene Therapy of Autosomal Recessive Congenital Ichthyosis and Other Types of Inherited Ichthyosis
by Daria S. Chulpanova, Alisa A. Shaimardanova, Aleksei S. Ponomarev, Somaia Elsheikh, Albert A. Rizvanov and Valeriya V. Solovyeva
Int. J. Mol. Sci. 2022, 23(5), 2506; https://doi.org/10.3390/ijms23052506 - 24 Feb 2022
Cited by 15 | Viewed by 6004
Abstract
Mutations in genes such as transglutaminase-1 (TGM1), which are responsible for the formation and normal functioning of a lipid barrier, lead to the development of autosomal recessive congenital ichthyosis (ARCI). ARCIs are characterized by varying degrees of hyperkeratosis and the presence [...] Read more.
Mutations in genes such as transglutaminase-1 (TGM1), which are responsible for the formation and normal functioning of a lipid barrier, lead to the development of autosomal recessive congenital ichthyosis (ARCI). ARCIs are characterized by varying degrees of hyperkeratosis and the presence of scales on the body surface since birth. The quality of life of patients is often significantly affected, and in order to alleviate the manifestations of the disease, symptomatic therapy with moisturizers, keratolytics, retinoids and other cosmetic substances is often used to improve the condition of the patients’ skin. Graft transplantation is commonly used to correct defects of the eye. However, these approaches offer symptomatic treatment that does not restore the lost protein function or provide a long-term skin barrier. Gene and cell therapies are evolving as promising therapy for ARCIs that can correct the functional activity of altered proteins. However, these approaches are still at an early stage of development. This review discusses current studies of gene and cell therapy approaches for various types of ichthyosis and their further prospects for patient treatment. Full article
(This article belongs to the Special Issue Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications 2.0)
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Other

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8 pages, 1950 KiB  
Case Report
Neither a Novel Tau Proteinopathy nor an Expansion of a Phenotype: Reappraising Clinicopathology-Based Nosology
by Luca Marsili, Jennifer Sharma, Alberto J. Espay, Alice Migazzi, Elhusseini Abdelghany, Emily J. Hill, Kevin R. Duque, Matthew C. Hagen, Christopher D. Stephen, Gabor G. Kovacs, Anthony E. Lang, Marios Hadjivassiliou, Manuela Basso, Marcelo A. Kauffman and Andrea Sturchio
Int. J. Mol. Sci. 2021, 22(14), 7292; https://doi.org/10.3390/ijms22147292 - 7 Jul 2021
Cited by 6 | Viewed by 2805
Abstract
The gold standard for classification of neurodegenerative diseases is postmortem histopathology; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia–ataxia syndrome with supranuclear gaze palsy, suspected to [...] Read more.
The gold standard for classification of neurodegenerative diseases is postmortem histopathology; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia–ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann–Pick disease Type C. Postmortem evaluation unexpectedly demonstrated neurodegeneration with 4-repeat tau deposition in a distribution diagnostic of progressive supranuclear palsy (PSP). Whole-exome sequencing revealed a new heterozygous variant in TGM6, associated with spinocerebellar ataxia type 35 (SCA35). This novel TGM6 variant reduced transglutaminase activity in vitro, suggesting it was pathogenic. This case could be interpreted as expanding: (1) the PSP phenotype to include a spinocerebellar variant; (2) SCA35 as a tau proteinopathy; or (3) TGM6 as a novel genetic variant underlying a SCA35 phenotype with PSP pathology. None of these interpretations seem adequate. We instead hypothesize that impairment in the crosslinking of tau by the TGM6-encoded transglutaminase enzyme may compromise tau functionally and structurally, leading to its aggregation in a pattern currently classified as PSP. The lessons from this case study encourage a reassessment of our clinicopathology-based nosology. Full article
(This article belongs to the Special Issue Transglutaminase Diseases, from the Experimental Laboratory to Human Pathology Applications 2.0)
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