The Actin and Tetraspanin Networks Organize Receptor Nanoclusters to Regulate B Cell Receptor-Mediated Signaling

Mattila, Pieta K.; Feest, Christoph; Depoil, David; Treanor, Bebhinn; Montaner, Beatriz; Otipoby, Kevin L.; Robert, Caroline; Justement, Louis B.; Bruckbauer, Andreas; Batista, Facundo D.

doi:10.1016/j.immuni.2012.11.019

Cited by 306 publications

(451 citation statements)

References 46 publications

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“…The proportion of confined α6 integrin is decreased by 75% on a mammary cell line upon CD151 knockdown, consistent with the idea that CD151 clusters the integrin within nanodomains [48]. Furthermore, CD19 lateral diffusion is increased by 2.5-fold on B cells from CD81-knockout mice [47]. It is proposed that CD81 confines CD19 into nanoclusters that can interact with activated B-cell receptors to promote signalling [47].…”

Section: Discussionsupporting

confidence: 62%

“…Furthermore, CD19 lateral diffusion is increased by 2.5-fold on B cells from CD81-knockout mice [47]. It is proposed that CD81 confines CD19 into nanoclusters that can interact with activated B-cell receptors to promote signalling [47]. The mechanisms by which tetraspanins exert their effects on partner protein dynamics are currently unknown.…”

Section: Discussionmentioning

confidence: 99%

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Tetraspanin Tspan9 regulates platelet collagen receptor GPVI lateral diffusion and activation

et al. 2016

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The tetraspanins are a superfamily of four-transmembrane proteins, which regulate the trafficking, lateral diffusion and clustering of the transmembrane proteins with which they interact. We have previously shown that tetraspanin Tspan9 is expressed on platelets. Here we have characterised gene-trap mice lacking Tspan9. The mice were viable with normal platelet numbers and size. Tspan9-deficient platelets were specifically defective in aggregation and secretion induced by the platelet collagen receptor GPVI, despite normal surface GPVI expression levels. A GPVI activation defect was suggested by partially impaired GPVI-induced protein tyrosine phosphorylation. In mechanistic experiments, Tspan9 and GPVI co-immunoprecipitated and co-localised, but super-resolution imaging revealed no defects in collagen-induced GPVI clustering on Tspan9-deficient platelets. However, single particle tracking using total internal reflection fluorescence microscopy showed that GPVI lateral diffusion was reduced by approximately 50% in the absence of Tspan9. Therefore, Tspan9 plays a fine-tuning role in platelet activation by regulating GPVI membrane dynamics.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Tetraspanin Tspan9 regulates platelet collagen receptor GPVI lateral diffusion and activation

et al. 2016

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“…On resting B cells, CD19 complex and the CD81‐tetraspanin complex are localized inside IgD‐class‐specific protein islands (Mattila et al , 2013; Maity et al , 2015). On activated B cells, however, the CD19 complex is found in close proximity to the open IgM‐BCR and thus gains access to ITAM signaling (Klasener et al , 2014).…”

Section: Introductionmentioning

confidence: 99%

Continuous signaling of CD 79b and CD 19 is required for the fitness of Burkitt lymphoma B cells

Kläsener

Iype

et al. 2018

The EMBO Journal

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Expression of the B‐cell antigen receptor (BCR) is essential not only for the development but also for the maintenance of mature B cells. Similarly, many B‐cell lymphomas, including Burkitt lymphoma (BL), require continuous BCR signaling for their tumor growth. This growth is driven by immunoreceptor tyrosine‐based activation motif (ITAM) and PI3 kinase (PI3K) signaling. Here, we employ CRISPR/Cas9 to delete BCR and B‐cell co‐receptor genes in the human BL cell line Ramos. We find that Ramos B cells require the expression of the BCR signaling component Igβ (CD79b), and the co‐receptor CD19, for their fitness and competitive growth in culture. Furthermore, we show that in the absence of any other BCR component, Igβ can be expressed on the B‐cell surface, where it is found in close proximity to CD19 and signals in an ITAM‐dependent manner. These data suggest that Igβ and CD19 are part of an alternative B‐cell signaling module that use continuous ITAM/PI3K signaling to promote the survival of B lymphoma and normal B cells.

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“…These studies have revealed that BCR microclusters function as a central platform for the signaling cascades that mediate B cell activation (3,16), which, in turn, are subject to the regulation imposed by CD19 and FcgRIIB. Batista and colleagues (17) were the first to report the key importance of BCR and CD19 microcluster colocalization in the initiation of BCR signaling, which has been advanced by their recent study using super-resolution microscopy to show the modestly concomitant concentration of BCR and CD19 molecules in Syk signaling microclusters upon BCR-Ag recognition (18).…”

mentioning

confidence: 99%

Through an ITIM-Independent Mechanism the FcγRIIB Blocks B Cell Activation by Disrupting the Colocalized Microclustering of the B Cell Receptor and CD19

Wang

et al. 2014

The Journal of Immunology

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B cell activation is regulated through the interplay of the BCR with the inhibitory coreceptor FcγRIIB and the activating coreceptor CD19. Recent studies suggest that Ag-driven BCR microclusters are efficiently converted to a signaling active state on colocalization with CD19 microclusters. Using total internal reflection fluorescence microscopy–based, high-resolution, high-speed live-cell and molecule imaging approaches, we show that when co-ligated to the BCR, the FcγRIIB can inhibit B cell activation by blocking the colocalization of BCR and CD19 microclusters within the B cell immunological synapse. Remarkably, this inhibitory function of FcγRIIB is dependent not on its well-characterized ITIM-containing cytoplasmic domain, but its transmembrane domain. Indeed, human primary B cells from systemic lupus erythematosus patients homozygous for gene encoding the loss-of-function transmembrane domain mutant FcγRIIB-I232T fail to block the synaptic colocalization of the BCR with CD19, leading to dysregulated recruitment of downstream signaling molecule p-PI3K to membrane proximal signalosome. This inhibitory function of FcγRIIB in impairing the spatial-temporal colocalization of BCR and CD19 microclusters in the B cell immunological synapse may help explain the hyper-reactive features of systemic lupus erythematosus patient B cells in reported studies. These observations may also provide new targets for therapies for systemic autoimmune disease.

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The Actin and Tetraspanin Networks Organize Receptor Nanoclusters to Regulate B Cell Receptor-Mediated Signaling

Cited by 306 publications

References 46 publications

Tetraspanin Tspan9 regulates platelet collagen receptor GPVI lateral diffusion and activation

Tetraspanin Tspan9 regulates platelet collagen receptor GPVI lateral diffusion and activation

Continuous signaling of CD 79b and CD 19 is required for the fitness of Burkitt lymphoma B cells

Through an ITIM-Independent Mechanism the FcγRIIB Blocks B Cell Activation by Disrupting the Colocalized Microclustering of the B Cell Receptor and CD19

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