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A truncated splice-variant of the Fc?RI? receptor subunit is critical for microtubule formation and degranulation in mast cells.

ABSTRACT: Human linkage analyses have implicated the MS4A2-containing gene locus (encoding Fc?RI?) as a candidate for allergy susceptibility. We have identified a truncation of Fc?RI? (t-Fc?RI?) in humans that contains a putative calmodulin-binding domain and thus, we sought to identify the role of this variant in mast cell function. We determined that t-Fc?RI? is critical for microtubule formation and degranulation and that it may perform this function by trafficking adaptor molecules and kinases to the pericentrosomal and Golgi region in response to Ca2+ signals. Mutagenesis studies suggest that calmodulin binding to t-Fc?RI? in the presence of Ca2+ could be critical for t-Fc?RI? function. In addition, gene targeting of t-Fc?RI? attenuated microtubule formation, degranulation, and IL-8 production downstream of Ca2+ signals. Therefore, t-Fc?RI? mediates Ca2+ -dependent microtubule formation, which promotes degranulation and cytokine release. Because t-Fc?RI? has this critical function, it represents a therapeutic target for the downregulation of allergic inflammation.

SUBMITTER: Cruse G

PROVIDER: S-EPMC3694348 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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A truncated splice-variant of the FcεRIβ receptor subunit is critical for microtubule formation and degranulation in mast cells.

Cruse Glenn G Beaven Michael A MA Ashmole Ian I Bradding Peter P Gilfillan Alasdair M AM Metcalfe Dean D DD

Immunity 20130502 5

Human linkage analyses have implicated the MS4A2-containing gene locus (encoding FcεRIβ) as a candidate for allergy susceptibility. We have identified a truncation of FcεRIβ (t-FcεRIβ) in humans that contains a putative calmodulin-binding domain and thus, we sought to identify the role of this variant in mast cell function. We determined that t-FcεRIβ is critical for microtubule formation and degranulation and that it may perform this function by trafficking adaptor molecules and kinases to the ...[more]

PMID: 23643722

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Project description:BackgroundUpon maturation in the bone marrow, polyploid megakaryocytes elongate very long and thin cytoplasmic branches called proplatelets. Proplatelets enter the sinusoids blood vessels in which platelets are ultimately released. Microtubule dynamics, bundling, sliding, and coiling, drive these dramatic morphological changes whose regulation remains poorly understood. Microtubule properties are defined by tubulin isotype composition and post-translational modification patterns. It remains unknown whether microtubule post-translational modifications occur in proplatelets and if so, whether they contribute to platelet formation.ResultsHere, we show that in proplatelets from mouse megakaryocytes, microtubules are both acetylated and polyglutamylated. To bypass the difficulties of working with differentiating megakaryocytes, we used a cell model that allowed us to test the functions of these modifications. First, we show that α2bβ3integrin signaling in D723H cells is sufficient to induce β1tubulin expression and recapitulate the specific microtubule behaviors observed during proplatelet elongation and platelet release. Using this model, we found that microtubule acetylation and polyglutamylation occur with different spatio-temporal patterns. We demonstrate that microtubule acetylation, polyglutamylation, and β1tubulin expression are mandatory for proplatelet-like elongation, swelling formation, and cytoplast severing. We discuss the functional importance of polyglutamylation of β1tubulin-containing microtubules for their efficient bundling and coiling during platelet formation.ConclusionsWe characterized and validated a powerful cell model to address microtubule behavior in mature megakaryocytes, which allowed us to demonstrate the functional importance of microtubule acetylation and polyglutamylation for platelet release. Furthermore, we bring evidence of a link between the expression of a specific tubulin isotype, the occurrence of microtubule post-translational modifications, and the acquisition of specific microtubule behaviors. Thus, our findings could widen the current view of the regulation of microtubule behavior in cells such as osteoclasts, spermatozoa, and neurons, which express distinct tubulin isotypes and display specific microtubule activities during differentiation.

Dataset Information

A truncated splice-variant of the Fc?RI? receptor subunit is critical for microtubule formation and degranulation in mast cells.

Publications

A truncated splice-variant of the FcεRIβ receptor subunit is critical for microtubule formation and degranulation in mast cells.

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