Protein sorting by lipid phase-like domains supports emergent signaling function in B lymphocyte plasma membranes

Stone, Matthew B.; Shelby, Sarah A.; Nunez, Marcos; Wisser, Kathleen; Veatch, Sarah L.

doi:10.7554/elife.19891

Cited by 208 publications

(268 citation statements)

References 91 publications

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“…Local exclusion of CD45 may take place even in the absence of KS as phosphorylated LAT can form a protein “phase” with other TCR signalosome components that can locally exclude the CD45 phosphatase domain 32 . Further, in the context of B cell antigen receptor cross-linking by antibodies, lipid phase separation generates nanoscale exclusion of CD45 33 . These effects, if active here, may reasonably have a strong dependence on lateral receptor packing and may contribute to the sharp signalling threshold on 3D surfaces.…”

Section: Ligand Spacing and Kinetic Segregationmentioning

confidence: 99%

Full control of ligand positioning reveals spatial thresholds for T cell receptor triggering

et al. 2018

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Elucidating the rules for receptor triggering in cell-cell and cell-matrix contacts requires precise control of ligand positioning in three dimensions. Here, we use the T cell receptor (TCR) as a model and subject T cells to different geometric arrangements of ligands, using a nanofabricated single-molecule array platform. This is comprised of monovalent TCR ligands anchored to lithographically patterned nanoparticle clusters surrounded by mobile adhesion molecules on a supported lipid bilayer (SLB). The TCR ligand could be co-planar with the SLB (2D), excluding the CD45 transmembrane tyrosine phosphatase, or elevated by 10 nm on solid nanopedestals (3D), allowing closer access of CD45 to engaged TCR. The two configurations resulted in different T cell responses, depending on the lateral spacing between the ligands. These results identify the important contributions of lateral and axial components of ligand positioning and create a more complete foundation for receptor engineering for immunotherapy.

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Section: Ligand Spacing and Kinetic Segregationmentioning

confidence: 99%

Full control of ligand positioning reveals spatial thresholds for T cell receptor triggering

et al. 2018

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“…The differential lipid order between lipid domains and the surrounding bulk membrane is thought to be highly relevant for cell physiology [1,2]. Accordingly, a recent study highlighted that lipid order differences arising from domain formation participate in selective sorting of membrane proteins [3].…”

Section: Introductionmentioning

confidence: 99%

“…Second, giant plasma membrane vesicles (GPMVs) derived from living cells [6] reveal that L o and L d phases in natural plasma membranes (PM) can assume a wide range of lipid order states resulting from lipid order tuning upon active cellular processes [7]. Third, cellular PMs exhibit regions of higher lipid order than the bulk lipids, either as small domains or larger areas depending on cellular processes [2,[8][9][10]. As an additional level of complexity, several studies on cells reveal the existence of lipid domains with a wider diversity of lipid composition, such as only partial sterol and SL co-enrichment [11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Tuning of Differential Lipid Order Between Submicrometric Domains and Surrounding Membrane Upon Erythrocyte Reshaping

Léonard

Pollet

Vermylen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Transient nanometric cholesterol- and sphingolipid-enriched domains, called rafts, are characterized by higher lipid order as compared to surrounding lipids. Here, we asked whether the seminal concept of highly ordered rafts could be refined with the presence of lipid domains exhibiting different enrichment in cholesterol and sphingomyelin and association with erythrocyte curvature areas. We also investigated how differences in lipid order between domains and surrounding membrane (bulk) are regulated and whether changes in order differences could participate to erythrocyte deformation and vesiculation. Methods: We used the fluorescent hydration- and membrane packing-sensitive probe Laurdan to determine by imaging mode the Generalized Polarization (GP) values of lipid domains vs the surrounding membrane. Results: Laurdan revealed the majority of sphingomyelin-enriched domains associated to low erythrocyte curvature areas and part of the cholesterol-enriched domains associated with high curvature. Both lipid domains were less ordered than the surrounding lipids in erythrocytes at resting state. Upon erythrocyte deformation (elliptocytes and stimulation of calcium exchanges) or membrane vesiculation (storage at 4°C), lipid domains became more ordered than the bulk. Upon aging and in membrane fragility diseases (spherocytosis), an increase in the difference of lipid order between domains and the surrounding lipids contributed to the initiation of domain vesiculation. Conclusion: The critical role of domain-bulk differential lipid order modulation for erythrocyte reshaping is discussed in relation with the pressure exerted by the cytoskeleton on the membrane.

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“…These domains are enriched in kinase and protected from phosphatase therefore facilitate ITAM phosphorylation and receptor activation. This mechanism is supported by a large quantity of past observations including those using detergent extraction (Yamanashi et al, 1991;Cheng et al, 1999), FRET imaging (Sohn et al, 2006;Sohn et al, 2008), and our recent study that utilized super-resolution fluorescence localization microscopy (Stone et al, 2017a). A second model of receptor activation, referred to as the transphosphorylation model, posits that kinases bound to receptors more effectively interact with and activate neighboring receptors when brought into close contact via a multivalent natural ligand or crosslinker (Pierce and Liu, 2010).…”

Section: Introductionmentioning

confidence: 82%

Membrane domains and phosphatase exclusion produce robust signaling responses in B cells engaged with natural ligands and artificial cross-linkers presented on lipid bilayers

Nunez

Wisser

Veatch

2019

Preprint

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B cells respond to a wide variety of antigens with varying valiancy and mode of presentation to the highly expressed B cell receptor (BCR). We previously demonstrated that clustering the IgM isotype of BCR with an artificial soluble cross-linker led to the stabilization of an ordered phase-like domain. This domain sorted minimal peptides and full-length proteins to generate local hot-spots for tyrosine phosphorylation at receptor clusters, facilitating receptor activation. BCR can also be activated through interactions with natural ligands or artificial cross-linkers presented at bilayer surfaces, where it is proposed that alternate mechanisms play important roles in receptor clustering and activation, including one mechanism involving the exclusion phosphatases due to their bulky extracellular domains.The goals of the current study are to determine if markers of membrane phases are sorted by BCR clusters formed through engagement with bilayer-presented natural ligands or cross-linkers, and to estimate the contribution that membrane phase partitioning plays in organizing regulatory proteins with respect to BCR clusters under these stimulation conditions. We use super-resolution fluorescence localization microscopy to find that BCR engagement with either a bilayer-presented natural ligand or artificial cross-linker generates ordered phase-like domains that are more robust than those observed with soluble cross-linkers. In addition, we provide evidence that interactions between regulatory proteins and BCR are partially determined through their preference for ordered membrane domains and present a minimal model of receptor activation that incorporates both ordered domains and steric exclusion mechanisms to produce a more sensitive response. Overall, this work highlights that cells are capable of integrating multiple interaction modalities to give rise to cellular functions, likely conferring flexibility and robustness to cellular responses.

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Protein sorting by lipid phase-like domains supports emergent signaling function in B lymphocyte plasma membranes

Cited by 208 publications

References 91 publications

Full control of ligand positioning reveals spatial thresholds for T cell receptor triggering

Full control of ligand positioning reveals spatial thresholds for T cell receptor triggering

Tuning of Differential Lipid Order Between Submicrometric Domains and Surrounding Membrane Upon Erythrocyte Reshaping

Membrane domains and phosphatase exclusion produce robust signaling responses in B cells engaged with natural ligands and artificial cross-linkers presented on lipid bilayers

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