Cellbiochemistry Research Laboratory
From left to right: Dr. B Tóth, Beáta; Dr. Mádi, András; Lénárt, Kinga; Dr. Kristóf, Endre; Csobán-Szabó, Zsuzsa; Dr. Király, Róbert; Prof. Fésüs, László; Vinnai, Boglárka; Csaholczi, Bianka; Arianti, Rini; Shaw, Abhirup; Nagy, Jennifer; Dr. Balajthy, Zoltán; Dr. Jambrovics, Károly; Vámos, Attila
Background
LÁSZLÓ FÉSÜS 
The research teams of the Laboratory of Cell Biochemistry has a strong track record in investigating biochemical features which determine cell fates and functions of differentiated cells. We have revealed critical molecular mechanisms in various cell death forms, such as apoptosis (billions of cells die daily by apoptosis in the human body), netosis, necroptosis and autophagic cell death, in the effectiveness of phagocytosis of the dying cells and the induction or suppression of inflammatory response to cell death. Important steps have been identified in the differentiation process of myeloid cells by studying promyelocytic cells responding to retinoic acid. New elements of thermogenesis regulation of human brown and beige adipocytes (thermogenic adipose tissue amounts up to 1.5% of total body mass in adult humans and can burn several kilograms of fat yearly by converting energy sources to heat in mitochondria) have been revealed and further investigated using primary cell cultures, single cell and gene expression analysis with the aim to find new ways in fighting obesity.
It has been one of the central elements of our biochemical approaches to understand the regulation, functions and pathologic roles of transglutaminases (humans have 7 catalytically active transglutaminases including blood coagulation factor 13A), particularly tissue transglutaminase (TG2). TG2 is a Ca2+-dependent multifunctional enzyme which can crosslink proteins (through glutamine and lysine residues), deamidate protein glutamines, serve as a G protein, interact with intra- and extracellular components, appear in various cell compartments and may initiate tissue fibrosis, neurodegeneration and coeliac disease. During the years we have clarified important structural and enzymatic features of TG2, described its epitopes recognized by coeliac antibodies, found constrain on its evolution in humans, revealed its importance in apoptosis and still aim to understand its general importance in basic cellular processes.
For details see our published articles at https://m2.mtmt.hu/gui2/?type=authors&mode=browse&sel=authors10000986&paging=2;20
Selected recent publications:
Kanchan K, Fuxreiter M, Fésüs L.(2015) Physiological, pathological, and structural implications of non-enzymatic protein-protein interactions of the multifunctional human transglutaminase 2. Cell Mol Life Sci 72: 3009-3035.
Arianti R, Vinnai BÁ, Tóth BB, Shaw A, Csősz É, Vámos A, Győry F, Fischer-Posovszky P, Wabitsch M, Kristóf E, Fésüs L. (2021) ASC-1 transporter-dependent amino acid uptake is required for the efficient thermogenic response of human adipocytes to adrenergic stimulation. FEBS Letts 595:2085-2098.
Rini Arianti PhD student, Prof. László Fésüs, Abhirup Shaw PhD student
2021 December
ZOLTÁN BALAJTHY 
We probe the basic mechanisms of differentiation of acute promyelocytic leukemia (APL) NB4 cells induced by all-trans retinoic acid (ATRA) in vitro and also in vivo. Dysregulated signaling pathway via overexpression of transglutaminase 2 promotes enhanced differentiation, capability of cell survival and intense cytokine storm. In this manner, it often contributes to the development of human diseases like different types of cancers, leukemia, neurodegenerative diseases or in the case of APL, differentiation syndrome. Our long-term goals are to identify and characterize those molecular mechanisms which are responsible for the development of TG2-dependent pathological diseases, with particular emphasis on APL pathogenesis.
Recent publications:.
Jambrovics K, Uray IP, Keressztesy Z, Keillor JW, Fésüs L, Balajthy Z. (2019) Transglutaminase 2 programs differentiating acute promyelocytic leukemia cells in all-trans retinoic acid treatment to inflammatory stage through NF-kB activation. Haematologica, 104: 505-515.
Jambrovics K, Uray IP, Keillor JW, Fésüs L, Balajthy Z (2020). Benefits of Combined All-Trans Retinoic Acid and Arsenic Trioxide Treatment of Acute Promyelocytic Leukemia Cells and Further Enhancement by Inhibition of Atypically Expressed Transglutaminase 2. Cancers (Basel). 12: 648.
ROBERT KIRÁLY 
Our work significantly contributed to revealing the Ca2+-binding sites of transglutaminase 2 and the epitopes of TG2 which are recognized by the antibodies which appear in coeliac disease patients. In recent years we have studied the still barely characterized isopeptidase activity of transglutaminase 2 and F13A due to potential therapeutic possibilities in reversing fibrosis, thrombosis and neurodegenerative diseases. We also performed the biochemical characterisation of human TG4, which could contribute to the high invasiveness of prostate cancer. Our current primary focus is the description of the TG2 interactome in endothelial cells (where TG2 is highly expressed but its role in this cell type is not known) using a recently developed human umbilical vein endothelial cell (HUVEC) model, which could also help the description of celiac cell phenotype.
Selected recent publications:
Csobán-Szabó Z, Fésüs L, Király R. (2020) Protein-peptide based assay for the characterization of human blood coagulation factor XIII-A isopeptidase activity. Anal Biochem. 600:113699.
Csobán-Szabó Z, Bécsi B, El Alaoui S, Fésüs L, Korponay-Szabó IR, Király R. (2021) Biochemical Characterisation of Human Transglutaminase 4. Int J Mol Sci. 22:12448.
Zsuzsa Csobán-Szabó PhD student, Róbert Király, Bianka Csaholczi PhD student
2021 December
ENDRE KRISTÓF 
Primarily, we aim to identify the unique molecular regulators of brown differentiation of human adipose-derived stromal cells and thermogenesis of the differentiated adipocytes obtained from adipose tissues of distinct anatomical origins by analyzing the global gene expression pattern of these cells. To prove that the identified molecular elements directly regulate brown/beige differentiation and/or activation, the specific genes will be deleted or overexpressed. Based on the obtained gene expression data, we wish to determine the secreted cytokine and metabolite profiles of distinct human thermogenic adipose tissues and adipocytes by system biology approaches. We also intend to systematically investigate how human browning adipocytes switch off their thermogenic capacity and become dormant in response to the withdrawal of browning-inducers. Our research might open up better strategies for specific stimulation of beneficial fat browning or preventing entry of potential brown adipocytes into dormancy in humans, which aid weight reduction and decrease insulin resistance in obese individuals.
Selected recent publications.
Kristóf E., Doan-Xuan Q. M., Bai P., Bacso Z., Fésüs L.(2015) Laser-scanning cytometry can quantify human adipocyte browning and proves effectiveness of irisin. Scientific Reports 5:12540.
Shaw A., Tóth B.B., Király R., Arianti R., Csomós I., Póliska S., Vámos A., Korponay-Szabó I.R., Bacso Z., Győry F., Fésüs L., Kristóf E. (2021) Irisin stimulates the release of CXCL1 from differentiating human subcutaneous and deep-neck derived adipocytes via upregulation of NFκB pathway. Front Cell Dev Biol 9:737872
ANDRÁS MÁDI 
We investigate the role of transglutaminase 2 in the functions of white adipose tissue of mice. We are interested in how this tissue type can support mice under the various stressful conditions in the absence of the enzyme. The studies include the artificial activation of adrenergic signaling pathways in animals using specific agonists. In addition, we study the browning process during which heat-producing, so-called “beige” cells are activated in this tissue by cold exposure.
Lénárt K, Pap A, Pórszász R, V Oláh A, Fésüs L, Mádi A. (2020) Transglutaminase 2 Has Metabolic and Vascular Regulatory Functions Revealed by In Vivo Activation of Alpha1-Adrenergic Receptor. Int J Mol Sci. 29:3865.
Mádi A, Cuaranta-Monroy I, Lénárt K, Pap A, Mezei ZA, Kristóf E, Oláh A, Vámosi G, Bacsó Z, Bai P, Fésüs L (2017) Browning deficiency and low mobilization of fatty acids in gonadal white adipose tissue leads to decreased cold-tolerance of transglutaminase 2 knock-out mice. Biochim Biophys Acta Mol Cell Biol Lipids. 1862:1575-1586.
BEATA B. TÓTH 
We investigate the exo- and endogenous regulatory factors (e.g., temperature, oxygen level, insulin level, hormones, signaling molecules, metabolites etc.) and signaling pathways related to the induction and coordinated operation of white and brown/beige adipocyte functions, and also to the transition between these phenotypes. We use primary human cells isolated from tissue samples and in vitro manipulate their condition to see their response mainly at gene-expression and protein level. Beside this, we apply in silico investigation of published database to test our hypothesis. Our results can elucidate the processes underlying metabolic diseases (eg.: Type 2 Diabetes, Insulin Resistance, Obesity, etc.) and may help identifying appropriate target molecules to develop effective and safe treatment.
Selected recent publications:
B. Tóth B, Barta Z, Barta ÁB, Fésüs L (2021) Regulatory modules of human thermogenic adipocytes: functional genomics of large cohort and Meta-analysis derived marker-genes BMC Genomics 22, 886.
Tóth BB, Arianti R, Shaw A, Vámos A, Veréb Z, Póliska S, Győry F, Bacso Z, Fésüs L, Kristóf E. (2020) FTO Intronic SNP Strongly Influences Human Neck Adipocyte Browning Determined by Tissue and PPARγ Specific Regulation: A Transcriptome Analysis. Cells. 9:987.
