![]() When inactive, ERM proteins adopt an auto-inhibited folded conformation, where the N- and C-termini interact to mask respective membrane- and F-actin-binding sites ( Gary and Bretscher, 1995). ERM proteins shuttle dynamically between active and inactive states, the balance of which is usually tipped one way or the other by a diverse range of extracellular input signals. ERM proteins can be structurally broken down into a band 4.1 ERM (FERM) N-terminal membrane-binding domain, a central α-helical domain and an acidic C-terminal actin-binding domain. Leukocytes express ezrin, moesin and negligible levels of radixin. For example, the ezrin/radixin/moesin (ERM) proteins link the plasma membrane and the underlying cortical actin-based cytoskeleton to mediate changes in cell shape ( Fehon et al., 2010 Ivetic and Ridley, 2004a). Following recruitment to activated endothelial monolayers, leukocytes undergo a series of dynamic changes in cell shape that are controlled by the coordinated actions of numerous cell adhesion molecules and underlying cytoskeletal proteins. Taken together, these results show that ezrin and moesin play mutually exclusive roles in modulating L-selectin signalling and shedding to control protrusion dynamics and polarity during monocyte TEM.Īn essential feature of acute inflammation is the migration of circulating innate immune cells, such as monocytes, towards damaged/infected tissue ( Nourshargh and Alon, 2014 Schimmel et al., 2017). In contrast, a non-cleavable L-selectin mutant binds selectively to ezrin, driving multi-pseudopodial extensions. The moesin–L-selectin interaction increases within transmigrated pseudopods as TEM proceeds, facilitating localised L-selectin ectodomain shedding. ![]() Ezrin binds preferentially to L-selectin in resting cells and during early TEM. Knockdown of ezrin, but not moesin, severely impaired the recruitment of monocytes to activated endothelial monolayers under flow, suggesting that this protein plays a unique role in the early recruitment process. Reactivation of ERM proteins within transmigrated pseudopods re-establishes their binding to targets, such as L-selectin. Here, we show that blocking binding of moesin to phosphatidylinositol 4,5-bisphosphate (PIP 2) reduces its C-terminal phosphorylation during monocyte TEM, and that on–off cycling of ERM activity is essential for pseudopod protrusion into the subendothelial space. The spatio-temporal organisation of ERM proteins with their targets, and their individual contribution to protrusion during TEM, has never been explored. Ezrin/radixin/moesin (ERM) proteins are expressed in leukocytes and mediate cell shape changes and polarity. Leukocyte transendothelial migration (TEM) is absolutely fundamental to the inflammatory response, and involves initial pseudopod protrusion and subsequent polarised migration across inflamed endothelium. A late night airport shuttle ride home descends into darkness.
0 Comments
Leave a Reply. |