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Conformational switching in ezrin regulates morphological and cytoskeletal changes required for B cell chemotaxis.

ABSTRACT: B cell chemotaxis occurs in response to specific chemokine gradients and is critical for homeostasis and immune response. The molecular regulation of B cell membrane-actin interactions during migration is poorly understood. In this study, we report a role for ezrin, a member of the membrane-cytoskeleton cross-linking ezrin-radixin-moesin proteins, in the regulation of the earliest steps of B cell polarization and chemotaxis. We visualized chemokine-induced changes in murine B cell morphology using scanning electron microscopy and spatiotemporal dynamics of ezrin in B cells using epifluorescence and total internal reflection microscopy. Upon chemokine stimulation, ezrin is transiently dephosphorylated to assume an inactive conformation and localizes to the lamellipodia. B cells expressing a phosphomimetic conformationally active mutant of ezrin or those in which ezrin dephosphorylation was pharmacologically inhibited displayed impaired microvillar dynamics, morphological polarization, and chemotaxis. Our data suggest a 2-fold involvement of ezrin in B cell migration, whereby it first undergoes chemokine-induced dephosphorylation to facilitate membrane flexibility, followed by relocalization to the actin-rich lamellipodia for dynamic forward protrusion of the cells.

SUBMITTER: Parameswaran N

PROVIDER: S-EPMC3106416 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Conformational switching in ezrin regulates morphological and cytoskeletal changes required for B cell chemotaxis.

Parameswaran Neetha N Matsui Ken K Gupta Neetu N

Journal of immunology (Baltimore, Md. : 1950) 20110221 7

B cell chemotaxis occurs in response to specific chemokine gradients and is critical for homeostasis and immune response. The molecular regulation of B cell membrane-actin interactions during migration is poorly understood. In this study, we report a role for ezrin, a member of the membrane-cytoskeleton cross-linking ezrin-radixin-moesin proteins, in the regulation of the earliest steps of B cell polarization and chemotaxis. We visualized chemokine-induced changes in murine B cell morphology usi ...[more]

PMID: 21339367

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Project description:Cellular entry of nonenveloped and enveloped viruses is often accompanied by dramatic conformational changes within viral structural proteins. These rearrangements are triggered by a variety of mechanisms, such as low pH, virus-receptor interactions, and virus-host chaperone interactions. Reoviruses, a model system for entry of nonenveloped viruses, undergo a series of disassembly steps within the host endosome. One of these steps, infectious subviral particle (ISVP)-to-ISVP* conversion, is necessary for delivering the genome-containing viral core into host cells, but the physiological trigger that mediates ISVP-to-ISVP* conversion during cell entry is unknown. Structural studies of the reovirus membrane penetration protein, ?1, predict that interactions between ?1 and negatively charged lipid head groups may promote ISVP* formation; however, experimental evidence for this idea is lacking. Here, we show that the presence of polyanions (SO4(2-) and HPO4(2-)) or lipids in the form of liposomes facilitates ISVP-to-ISVP* conversion. The requirement for charged lipids appears to be selective, since phosphatidylcholine and phosphatidylethanolamine promoted ISVP* formation, whereas other lipids, such as sphingomyelin and sulfatide, either did not affect ISVP* formation or prevented ISVP* formation. Thus, our work provides evidence that interactions with membranes can function as a trigger for a nonenveloped virus to gain entry into host cells.Cell entry, a critical stage in the virus life cycle, concludes with the delivery of the viral genetic material across host membranes. Regulated structural transitions within nonenveloped and enveloped viruses are necessary for accomplishing this step; these conformational changes are predominantly triggered by low pH and/or interactions with host proteins. In this work, we describe a previously unknown trigger, interactions with lipid membranes, which can induce the structural rearrangements required for cell entry. This mechanism operates during entry of mammalian orthoreoviruses. We show that interactions between reovirus entry intermediates and lipid membranes devoid of host proteins promote conformational changes within the viral outer capsid that lead to membrane penetration. Thus, this work illustrates a novel strategy that nonenveloped viruses can use to gain access into cells and how viruses usurp disparate host factors to initiate infection.

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Conformational switching in ezrin regulates morphological and cytoskeletal changes required for B cell chemotaxis.

Publications

Conformational switching in ezrin regulates morphological and cytoskeletal changes required for B cell chemotaxis.

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