Signaling Function of PRC2 is Essential for TCR-driven T Cell Responses

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2018 Mar 11

PMID 29523590

Citations 25

Authors

Marc-Werner Dobenecker

Joon Seok Park

Jonas Marcello

Michael T McCabe

Richard Gregory

Steven D Knight

Inmaculada Rioja

Anna K Bassil

Rabinder K Prinjha

Alexander Tarakhovsky

Affiliations

Soon will be listed here.

Abstract

Differentiation and activation of T cells require the activity of numerous histone lysine methyltransferases (HMT) that control the transcriptional T cell output. One of the most potent regulators of T cell differentiation is the HMT Ezh2. Ezh2 is a key enzymatic component of polycomb repressive complex 2 (PRC2), which silences gene expression by histone H3 di/tri-methylation at lysine 27. Surprisingly, in many cell types, including T cells, Ezh2 is localized in both the nucleus and the cytosol. Here we show the presence of a nuclear-like PRC2 complex in T cell cytosol and demonstrate a role of cytosolic PRC2 in T cell antigen receptor (TCR)-mediated signaling. We show that short-term suppression of PRC2 precludes TCR-driven T cell activation in vitro. We also demonstrate that pharmacological inhibition of PRC2 in vivo greatly attenuates the severe T cell-driven autoimmunity caused by regulatory T cell depletion. Our data reveal cytoplasmic PRC2 is one of the most potent regulators of T cell activation and point toward the therapeutic potential of PRC2 inhibitors for the treatment of T cell-driven autoimmune diseases.

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References

Beguelin W, Popovic R, Teater M, Jiang Y, Bunting K, Rosen M . EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 2013; 23(5):677-92. PMC: 3681809. DOI: 10.1016/j.ccr.2013.04.011. View

Gunawan M, Venkatesan N, Loh J, Wong J, Berger H, Neo W . The methyltransferase Ezh2 controls cell adhesion and migration through direct methylation of the extranuclear regulatory protein talin. Nat Immunol. 2015; 16(5):505-16. DOI: 10.1038/ni.3125. View

Katzav S . Flesh and blood: the story of Vav1, a gene that signals in hematopoietic cells but can be transforming in human malignancies. Cancer Lett. 2007; 255(2):241-54. DOI: 10.1016/j.canlet.2007.04.015. View

Yang X, Jiang K, Hirahara K, Vahedi G, Afzali B, Sciume G . EZH2 is crucial for both differentiation of regulatory T cells and T effector cell expansion. Sci Rep. 2015; 5:10643. PMC: 4473539. DOI: 10.1038/srep10643. View

Su I, Tarakhovsky A . Lysine methylation and 'signaling memory'. Curr Opin Immunol. 2006; 18(2):152-7. DOI: 10.1016/j.coi.2006.01.012. View

Margueron R, Reinberg D . The Polycomb complex PRC2 and its mark in life. Nature. 2011; 469(7330):343-9. PMC: 3760771. DOI: 10.1038/nature09784. View

Dower N, Stang S, Bottorff D, Ebinu J, Dickie P, Ostergaard H . RasGRP is essential for mouse thymocyte differentiation and TCR signaling. Nat Immunol. 2001; 1(4):317-21. DOI: 10.1038/79766. View

Whitehurst C, Geppert T . MEK1 and the extracellular signal-regulated kinases are required for the stimulation of IL-2 gene transcription in T cells. J Immunol. 1996; 156(3):1020-9. View

Cao R, Zhang Y . The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr Opin Genet Dev. 2004; 14(2):155-64. DOI: 10.1016/j.gde.2004.02.001. View

10.

Konze K, Ma A, Li F, Barsyte-Lovejoy D, Parton T, MacNevin C . An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1. ACS Chem Biol. 2013; 8(6):1324-34. PMC: 3773059. DOI: 10.1021/cb400133j. View

11.

Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg S . TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013; 14(4):R36. PMC: 4053844. DOI: 10.1186/gb-2013-14-4-r36. View

12.

Lee J, Lee J, Kim H, Kim K, Park H, Kim J . EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex. Mol Cell. 2012; 48(4):572-86. DOI: 10.1016/j.molcel.2012.09.004. View

13.

Bennett C, Christie J, Ramsdell F, Brunkow M, Ferguson P, Whitesell L . The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001; 27(1):20-1. DOI: 10.1038/83713. View

14.

Trapnell C, Hendrickson D, Sauvageau M, Goff L, Rinn J, Pachter L . Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat Biotechnol. 2012; 31(1):46-53. PMC: 3869392. DOI: 10.1038/nbt.2450. View

15.

Kim J, Rasmussen J, Rudensky A . Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol. 2006; 8(2):191-7. DOI: 10.1038/ni1428. View

16.

Thorvaldsdottir H, Robinson J, Mesirov J . Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform. 2012; 14(2):178-92. PMC: 3603213. DOI: 10.1093/bib/bbs017. View

17.

Goldberg A, Banaszynski L, Noh K, Lewis P, Elsaesser S, Stadler S . Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell. 2010; 140(5):678-91. PMC: 2885838. DOI: 10.1016/j.cell.2010.01.003. View

18.

Bustelo X . Vav family exchange factors: an integrated regulatory and functional view. Small GTPases. 2014; 5(2):9. PMC: 4601183. DOI: 10.4161/21541248.2014.973757. View

19.

Dobenecker M, Kim J, Marcello J, Fang T, Prinjha R, Bosselut R . Coupling of T cell receptor specificity to natural killer T cell development by bivalent histone H3 methylation. J Exp Med. 2015; 212(3):297-306. PMC: 4354372. DOI: 10.1084/jem.20141499. View

20.

Brunkow M, Jeffery E, Hjerrild K, Paeper B, Clark L, Yasayko S . Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001; 27(1):68-73. DOI: 10.1038/83784. View