The methyltransferase Ezh2 controls cell adhesion and migration through direct methylation of the extranuclear regulatory protein talin.
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.
School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
Merry
M
Gunawan
School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
Nandini
N
Venkatesan
School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
Jia Tong
JT
Loh
School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
Jong Fu
JF
Wong
School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
Heidi
H
Berger
School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
Wen Hao
0000000244854118
WH
Neo
Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis, Republic of Singapore.
Liang Yao Jackson
LY
Li
School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
Myint Khun
MK
La Win
School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
Yin Hoe
YH
Yau
School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
Tiannan
T
Guo
Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis, Republic of Singapore.
Peter Chi Ee
PC
See
Department of immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Sayuri
S
Yamazaki
1] Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Republic of Singapore. [2] Institute of Molecular &Cell Biology, Agency for Science and Technology Research, Republic of Singapore.
Keh Chuang
KC
Chin
Department of Medicine, University of California San Diego, La Jolla, California, USA.
Alexandre R
AR
Gingras
School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
Susana Geifman
SG
Shochat
Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis, Republic of Singapore.
Lai Guan
LG
Ng
School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
Siu Kwan
0000000256521687
SK
Sze
Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis, Republic of Singapore.
Florent
0000000228577755
F
Ginhoux
School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
I-hsin
IH
Su
D000199:Actins / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D000071221:Enhancer of Zeste Homolog 2 Protein; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D016608:Talin / Q000235:genetics / Q000378:metabolism*; D057705:Transendothelial and Transepithelial Migration / Q000235:genetics
D000199:Actins; D051567:Proto-Oncogene Proteins c-vav; D016608:Talin; C496619:Vav1 protein, mouse; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2