The Methyltransferase Ezh2 Controls Cell Adhesion and Migration Through Direct Methylation of the Extranuclear Regulatory Protein Talin

Overview

Journal Nat Immunol

Date 2015 Mar 10

PMID 25751747

Citations 92

Authors

Merry Gunawan

Nandini Venkatesan

Jia Tong Loh

Jong Fu Wong

Heidi Berger

Wen Hao Neo

Liang Yao Jackson Li

Myint Khun La Win

Yin Hoe Yau

Tiannan Guo

Peter Chi Ee See

Sayuri Yamazaki

Keh Chuang Chin

Alexandre R Gingras

Susana Geifman Shochat

Lai Guan Ng

Siu Kwan Sze

Florent Ginhoux

I-Hsin Su

Affiliations

Soon will be listed here.

Abstract

A cytosolic role for the histone methyltransferase Ezh2 in regulating lymphocyte activation has been suggested, but the molecular mechanisms underpinning this extranuclear function have remained unclear. Here we found that Ezh2 regulated the integrin signaling and adhesion dynamics of neutrophils and dendritic cells (DCs). Ezh2 deficiency impaired the integrin-dependent transendothelial migration of innate leukocytes and restricted disease progression in an animal model of multiple sclerosis. Direct methylation of talin, a key regulatory molecule in cell migration, by Ezh2 disrupted the binding of talin to F-actin and thereby promoted the turnover of adhesion structures. This regulatory effect was abolished by targeted disruption of the interactions of Ezh2 with the cytoskeletal-reorganization effector Vav1. Our studies reveal an unforeseen extranuclear function for Ezh2 in regulating adhesion dynamics, with implications for leukocyte migration, immune responses and potentially pathogenic processes.

Citing Articles

Polycomb repressive complex 2 (PRC2) pathway's role in cancer cell plasticity and drug resistance.

Goleij P, Heidari M, Tabari M, Hadipour M, Rezaee A, Javan A Funct Integr Genomics. 2025; 25(1):53.

PMID: 40048009 DOI: 10.1007/s10142-025-01563-8.

The epigenetic hallmarks of immune cells in cancer.

Ji Y, Xiao C, Fan T, Deng Z, Wang D, Cai W Mol Cancer. 2025; 24(1):66.

PMID: 40038722 PMC: 11881328. DOI: 10.1186/s12943-025-02255-4.

Enhancer zeste homolog 2 (EZH2) targeting by small interfering RNA (siRNA); recent advances and prospect.

Hsu C, Mohammed A, Hjazi A, Uthirapathy S, Renuka J, Singh A Naunyn Schmiedebergs Arch Pharmacol. 2025; .

PMID: 39960560 DOI: 10.1007/s00210-025-03883-9.

ROS regulates circadian rhythms by modulating Ezh2 interactions with clock proteins.

Zhang H, Li K, Wang Y, Wei C, Gao Y, Ren-Zhou Redox Biol. 2025; 81:103526.

PMID: 39952198 PMC: 11875201. DOI: 10.1016/j.redox.2025.103526.

Exploring oncogenic roles and clinical significance of EZH2: focus on non-canonical activities.

Wozniak M, Czyz M Ther Adv Med Oncol. 2025; 17():17588359241306026.

PMID: 39776536 PMC: 11705335. DOI: 10.1177/17588359241306026.

References

Goksoy E, Ma Y, Wang X, Kong X, Perera D, Plow E . Structural basis for the autoinhibition of talin in regulating integrin activation. Mol Cell. 2008; 31(1):124-33. PMC: 2522368. DOI: 10.1016/j.molcel.2008.06.011. View

Kruidenier L, Chung C, Cheng Z, Liddle J, Che K, Joberty G . A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature. 2012; 488(7411):404-8. PMC: 4691848. DOI: 10.1038/nature11262. View

Ren X, Kiosses W, Sieg D, Otey C, Schlaepfer D, Schwartz M . Focal adhesion kinase suppresses Rho activity to promote focal adhesion turnover. J Cell Sci. 2000; 113 ( Pt 20):3673-8. DOI: 10.1242/jcs.113.20.3673. View

Coxon A, Rieu P, Barkalow F, Askari S, Sharpe A, von Andrian U . A novel role for the beta 2 integrin CD11b/CD18 in neutrophil apoptosis: a homeostatic mechanism in inflammation. Immunity. 1996; 5(6):653-66. DOI: 10.1016/s1074-7613(00)80278-2. View

Bedford M, Clarke S . Protein arginine methylation in mammals: who, what, and why. Mol Cell. 2009; 33(1):1-13. PMC: 3372459. DOI: 10.1016/j.molcel.2008.12.013. View

Pendl G, Robert C, Steinert M, Thanos R, Eytner R, Borges E . Immature mouse dendritic cells enter inflamed tissue, a process that requires E- and P-selectin, but not P-selectin glycoprotein ligand 1. Blood. 2002; 99(3):946-56. DOI: 10.1182/blood.v99.3.946. View

Zhang F, Saha S, Kashina A . Arginylation-dependent regulation of a proteolytic product of talin is essential for cell-cell adhesion. J Cell Biol. 2012; 197(6):819-36. PMC: 3373405. DOI: 10.1083/jcb.201112129. View

van der Vlag J, Otte A . Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nat Genet. 1999; 23(4):474-8. DOI: 10.1038/70602. View

Kontaki H, Talianidis I . Lysine methylation regulates E2F1-induced cell death. Mol Cell. 2010; 39(1):152-60. DOI: 10.1016/j.molcel.2010.06.006. View

10.

Garcia-Bernal D, Parmo-Cabanas M, Dios-Esponera A, Samaniego R, Hernan-P de la Ossa D, Teixido J . Chemokine-induced Zap70 kinase-mediated dissociation of the Vav1-talin complex activates alpha4beta1 integrin for T cell adhesion. Immunity. 2009; 31(6):953-64. DOI: 10.1016/j.immuni.2009.09.021. View

11.

Abram C, Lowell C . The ins and outs of leukocyte integrin signaling. Annu Rev Immunol. 2009; 27:339-62. PMC: 3248397. DOI: 10.1146/annurev.immunol.021908.132554. View

12.

Ezhkova E, Pasolli H, Parker J, Stokes N, Su I, Hannon G . Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell. 2009; 136(6):1122-35. PMC: 2716120. DOI: 10.1016/j.cell.2008.12.043. View

13.

Alon R, Dustin M . Force as a facilitator of integrin conformational changes during leukocyte arrest on blood vessels and antigen-presenting cells. Immunity. 2007; 26(1):17-27. DOI: 10.1016/j.immuni.2007.01.002. View

14.

Lammermann T, Bader B, Monkley S, Worbs T, Wedlich-Soldner R, Hirsch K . Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature. 2008; 453(7191):51-5. DOI: 10.1038/nature06887. View

15.

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

16.

Chuikov S, Kurash J, Wilson J, Xiao B, Justin N, Ivanov G . Regulation of p53 activity through lysine methylation. Nature. 2004; 432(7015):353-60. DOI: 10.1038/nature03117. View

17.

Springer T, Dustin M . Integrin inside-out signaling and the immunological synapse. Curr Opin Cell Biol. 2011; 24(1):107-15. PMC: 3294052. DOI: 10.1016/j.ceb.2011.10.004. View

18.

Tran A, Marmo T, Salam A, Che S, Finkelstein E, Kabarriti R . HDAC6 deacetylation of tubulin modulates dynamics of cellular adhesions. J Cell Sci. 2007; 120(Pt 8):1469-79. DOI: 10.1242/jcs.03431. View

19.

Czermin B, Melfi R, McCabe D, Seitz V, Imhof A, Pirrotta V . Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell. 2002; 111(2):185-96. DOI: 10.1016/s0092-8674(02)00975-3. View

20.

Ross T, Coon B, Yun S, Baeyens N, Tanaka K, Ouyang M . Integrins in mechanotransduction. Curr Opin Cell Biol. 2013; 25(5):613-8. PMC: 3757118. DOI: 10.1016/j.ceb.2013.05.006. View