Transglutaminase 2 (TG2) mediates protein modifications by crosslinking or by incorporating polyamine in response to oxidative or DNA-damaging stress, thereby regulating apoptosis, extracellular matrix formation, and inflammation. The regulation of transcriptional activity by TG2-mediated histone serotonylation or by Sp1 crosslinking may also contribute to cellular stress responses.
In this study, we attempted to identify TG2-interacting proteins to better understand the role of TG2 in transcriptional regulation.
Using a yeast two-hybrid assay to screen a HeLa cell cDNA library, we found that TG2 bound BAF250a, a core subunit of the cBAF chromatin remodeling complex, through an interaction between the TG2 barrel 1 and BAF250a C-terminal domains.
TG2 was pulled down with a GST-BAF250a C-term fusion protein. Moreover, TG2 and BAF250a were co-fractionated using P11 chromatography, and co-immunoprecipitated. A transamidation reaction showed that TG2 mediated incorporation of polyamine into BAF250a. In glucocorticoid response-element reporter-expressing cells, TG2 overexpression increased the luciferase reporter activity in a transamidation-dependent manner. In addition, a comparison of genome-wide gene expression between wild-type and TG2-deficient primary hepatocytes in response to dexamethasone treatment showed that TG2 further enhanced or suppressed the expression of dexamethasone-regulated genes that were identified by a gene ontology enrichment analysis.
Thus, our results indicate that TG2 regulates transcriptional activity through BAF250a polyamination.
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Aeschlimann D et al (1998) Isolation of a cDNA encoding a novel member of the transglutaminase gene family from human keratinocytes. Detection and identification of transglutaminase gene products based on reverse transcription-polymerase chain reaction with degenerate primers. J Biol Chem 273:3452–3460. https://doi.org/10.1074/jbc.273.6.3452
Ai L et al (2008) The transglutaminase 2 gene (TGM2), a potential molecular marker for chemotherapeutic drug sensitivity, is epigenetically silenced in breast cancer. Carcinogenesis 29:510–518. https://doi.org/10.1093/carcin/bgm280
Cho SY et al (2020) Transglutaminase 2 mediates hypoxia-induced selective mRNA translation via polyamination of 4EBPs. Life Sci Alliance. https://doi.org/10.26508/lsa.201900565
Choi K et al (2005) Chemistry and biology of dihydroisoxazole derivatives: selective inhibitors of human transglutaminase 2. Chem Biol 12:469–475. https://doi.org/10.1016/j.chembiol.2005.02.007
De Laurenzi V, Melino G (2001) Gene disruption of tissue transglutaminase. Mol Cell Biol 21:148–155. https://doi.org/10.1128/mcb.21.1.148-155.2001
Farrelly LA et al (2019) Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature 567:535–539. https://doi.org/10.1038/s41586-019-1024-7
Fryer CJ, Archer TK (1998) Chromatin remodelling by the glucocorticoid receptor requires the BRG1 complex. Nature 393:88–91. https://doi.org/10.1038/30032
Jang GY et al (2010) Transglutaminase 2 suppresses apoptosis by modulating caspase 3 and NF-kappaB activity in hypoxic tumor cells. Oncogene 29:356–367. https://doi.org/10.1038/onc.2009.342
Jeon JH et al (2003a) Transglutaminase 2 inhibits Rb binding of human papillomavirus E7 by incorporating polyamine. EMBO J 22:5273–5282. https://doi.org/10.1093/emboj/cdg495
Jeon JH et al (2003b) Differential incorporation of biotinylated polyamines by transglutaminase 2. FEBS Lett 534:180–184. https://doi.org/10.1016/s0014-5793(02)03836-x
Jeon BH, Yoo YM, Jung EM, Jeung EB (2020) Dexamethasone treatment increases the intracellular calcium level through TRPV6 in A549 cells. Int J Mol Sci. https://doi.org/10.3390/ijms21031050
Kozmik Z et al (2001) Characterization of mammalian orthologues of the Drosophila osa gene: cDNA cloning, expression, chromosomal localization, and direct physical interaction with Brahma chromatin-remodeling complex. Genomics 73:140–148. https://doi.org/10.1006/geno.2001.6477
Lee SM et al (2012) Cysteamine prevents the development of lens opacity in a rat model of selenite-induced cataract. Investig Ophthalmol Vis Sci 53:1452–1459. https://doi.org/10.1167/iovs.11-8636
Lee JH et al (2014) Endoplasmic reticulum stress activates transglutaminase 2 leading to protein aggregation. Int J Mol Med 33:849–855. https://doi.org/10.3892/ijmm.2014.1640
Lee SJ et al (2017) Transglutaminase 2 mediates UV-induced skin inflammation by enhancing inflammatory cytokine production. Cell Death Dis 8:e3148. https://doi.org/10.1038/cddis.2017.550
Masliah-Planchon J et al (2015) SWI/SNF chromatin remodeling and human malignancies. Annu Rev Pathol 10:145–171. https://doi.org/10.1146/annurev-pathol-012414-040445
Mathur R, Roberts CWM (2018) SWI/SNF (BAF) complexes: guardians of the epigenome. Annu Rev Cancer Biol 2:413–427. https://doi.org/10.1146/annurev-cancerbio-030617-050151
McConoughey SJ et al (2010) Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease. EMBO Mol Med 2:349–370. https://doi.org/10.1002/emmm.201000084
Mehta K, Kumar A, Kim HI (2010) Transglutaminase 2: a multi-tasking protein in the complex circuitry of inflammation and cancer. Biochem Pharmacol 80:1921–1929. https://doi.org/10.1016/j.bcp.2010.06.029
Mittal P, Roberts CWM (2020) The SWI/SNF complex in cancer - biology, biomarkers and therapy. Nat Rev Clin Oncol 17:435–448. https://doi.org/10.1038/s41571-020-0357-3
Muratcioglu S et al (2015) Structural Modeling of GR Interactions with the SWI/SNF Chromatin Remodeling Complex and C/EBP. Biophys J 109:1227–1239. https://doi.org/10.1016/j.bpj.2015.06.044
Myneni VD, Melino G, Kaartinen MT (2015) Transglutaminase 2–a novel inhibitor of adipogenesis. Cell Death Dis 6:e1868. https://doi.org/10.1038/cddis.2015.238
Nanda N et al (2001) Targeted inactivation of Gh/tissue transglutaminase II. J Biol Chem 276:20673–20678. https://doi.org/10.1074/jbc.M010846200
Nie Z et al (2000) A specificity and targeting subunit of a human SWI/SNF family-related chromatin-remodeling complex. Mol Cell Biol 20:8879–8888. https://doi.org/10.1128/mcb.20.23.8879-8888.2000
Olsen KC et al (2011) Transglutaminase 2 and its role in pulmonary fibrosis. Am J Respir Crit Care Med 184:699–707. https://doi.org/10.1164/rccm.201101-0013OC
Sandhya S et al (2018) Domain architecture of BAF250a reveals the ARID and ARM-repeat domains with implication in function and assembly of the BAF remodeling complex. PLoS ONE 13:e0205267. https://doi.org/10.1371/journal.pone.0205267
Shin DM et al (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 279:15032–15039. https://doi.org/10.1074/jbc.M308734200
Shin DM et al (2008) Cystamine prevents ischemia-reperfusion injury by inhibiting polyamination of RhoA. Biochem Biophys Res Commun 365:509–514. https://doi.org/10.1016/j.bbrc.2007.11.007
Shin JW et al (2020) Keratinocyte transglutaminase 2 promotes CCR6(+) γδT-cell recruitment by upregulating CCL20 in psoriatic inflammation. Cell Death Dis 11:301. https://doi.org/10.1038/s41419-020-2495-z
Szondy Z et al (2003) Transglutaminase 2-/- mice reveal a phagocytosis-associated crosstalk between macrophages and apoptotic cells. Proc Natl Acad Sci USA 100:7812–7817. https://doi.org/10.1073/pnas.0832466100
Tang L, Nogales E, Ciferri C (2010) Structure and function of SWI/SNF chromatin remodeling complexes and mechanistic implications for transcription. Prog Biophys Mol Biol 102:122–128. https://doi.org/10.1016/j.pbiomolbio.2010.05.001
Tatsukawa H et al (2009) Role of transglutaminase 2 in liver injury via cross-linking and silencing of transcription factor Sp1. Gastroenterology 136:1783-1795.e1710. https://doi.org/10.1053/j.gastro.2009.01.007
Tatsukawa H et al (2016) Transglutaminase 2 has opposing roles in the regulation of cellular functions as well as cell growth and death. Cell Death Dis 7:e2244. https://doi.org/10.1038/cddis.2016.150
Tordjmann T et al (1997) An improved digitonin-collagenase perfusion technique for the isolation of periportal and perivenous hepatocytes from a single rat liver: physiological implications for lobular heterogeneity. Hepatology (Baltimore, MD) 26:1592–1599. https://doi.org/10.1053/jhep.1997.v26.pm0009398003
Verderio EA, Johnson TS, Griffin M (2005) Transglutaminases in wound healing and inflammation. Prog Exp Tumor Res 38:89–114. https://doi.org/10.1159/000084235
Vihervaara A, Duarte FM, Lis JT (2018) Molecular mechanisms driving transcriptional stress responses. Nat Rev Genet 19:385–397. https://doi.org/10.1038/s41576-018-0001-6
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. https://doi.org/10.1074/jbc.273.4.2288
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (grant No. 2012R1A1A2005188 and 2017R1C1B2002183); and the Bio & Medical Technology Development Program of the NRF funded by the Ministry of Science & ICT (grant No. 2018M3A9F3056902).
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Kim, HJ., Lee, JH., Cho, SY. et al. Transglutaminase 2 mediates transcriptional regulation through BAF250a polyamination. Genes Genom (2021). https://doi.org/10.1007/s13258-021-01055-6
- Transglutaminase 2 (TG2)
- Transcriptional activity