Transglutaminase 2 mediates transcriptional regulation through BAF250a polyamination

Abstract

Background

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.

Objective

In this study, we attempted to identify TG2-interacting proteins to better understand the role of TG2 in transcriptional regulation.

Methods

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.

Results

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.

Conclusion

Thus, our results indicate that TG2 regulates transcriptional activity through BAF250a polyamination.

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References

  1. 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

    CAS  Article  PubMed  Google Scholar 

  2. 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

    CAS  Article  PubMed  Google Scholar 

  3. 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

    Article  PubMed  PubMed Central  Google Scholar 

  4. 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

    CAS  Article  PubMed  Google Scholar 

  5. 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

    Article  PubMed  PubMed Central  Google Scholar 

  6. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Article  PubMed  Google Scholar 

  8. 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

    CAS  Article  PubMed  Google Scholar 

  9. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 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

    CAS  Article  PubMed  Google Scholar 

  11. 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

    Article  PubMed  PubMed Central  Google Scholar 

  12. 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

    CAS  Article  PubMed  Google Scholar 

  13. 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

    CAS  Article  Google Scholar 

  14. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 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

    CAS  Article  PubMed  Google Scholar 

  17. 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

    Article  Google Scholar 

  18. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 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

    CAS  Article  PubMed  Google Scholar 

  20. 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

    CAS  Article  PubMed  Google Scholar 

  21. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 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

    CAS  Article  PubMed  Google Scholar 

  24. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 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

    CAS  Article  PubMed  Google Scholar 

  28. 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

    CAS  Article  PubMed  Google Scholar 

  29. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 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

    CAS  Article  PubMed  Google Scholar 

  31. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 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

    CAS  Article  Google Scholar 

  35. 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

    CAS  Article  PubMed  Google Scholar 

  36. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 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

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

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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Authors

Contributions

JHJ and IGK conceived and designed the experiments. HJK, JHL and SYC performed the experiments and collected the data. IGK wrote the manuscript with assistance and final approval by all the coauthors.

Corresponding author

Correspondence to In-Gyu Kim.

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The authors declare that they have no conflicts of interest.

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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

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Keywords

  • Transglutaminase 2 (TG2)
  • BAF250a
  • Transamidation
  • Dexamethasone
  • Transcriptional activity