The methyltransferase Ezh2 controls cell adhesion and migration through direct methylation of the extranuclear regulatory protein talin

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.

Cellular and molecular regulation of innate inflammatory responses

“…60,61 The conventional PTMs such as ubiquitination and phosphorylation and unconventional PTMs such as methylation, acetylation and sumoylation target nearly all critical components of PRR signaling, such as receptors, adaptors, enzymes and transcriptional factors to modulate the quality of PRR signals. [62][63][64][65] Taking PTM control of TLR-triggered tumor necrosis factor receptor-associated factor 6 (TRAF6)/NF-κB signaling pathway as an example. Removal of K63-linked polyubiquitination by A20 66 and TRAF family member-associated NF-κB activator (TANK) 67 is shown to modulate TRAF6 activity for inhibition of TLR signaling activation.…”

Neutrophil recruitment limited by high-affinity bent β2 integrin binding ligand in cis

“…Delay in neutrophil recovery is the main reason for lethal infections in patients receiving allogeneic haematopoietic stem cell transplantation8. Neutrophils are also important in non-infectious or chronic inflammation such as injury-induced sterile inflammation9, and in autoimmune diseases, including rheumatoid arthritis10, multiple sclerosis11 and systemic lupus erythematosus12.…”

Post-translational modification-regulated leukocyte adhesion and migration

“…This modified talin fragment is found to be essential for the formation of cadherin-dependent cell-cell adhesion [49]. More recently, we have identified a talin methylation site on Lys-2454 that plays a critical role in the regulation of leukocyte migration [50]. Methylated talin exhibits reduced binding affinity for F-actin, which promotes the disassembly of adhesion structures and facilitates cellular migration.…”

“…This recruitment promotes the direct methylation of talin, which alters the binding of talin to filamentous actin and exerts a major influence on cell migration and adhesion dynamics [50]. Our initial observation was that Ezh2-deficient bone marrow-derived mature dendritic cells (DCs) exhibited significantly reduced migratory capacity on integrin ligand coated surfaces compared to control cells.…”