B Cell Receptor-Mediated Antigen Gathering Requires Ubiquitin Ligase Cbl and Adaptors Grb2 and Dok-3 to Recruit Dynein to the Signaling Microcluster

Schnyder, Tim; Castello, Angelo; Feest, Christoph; Harwood, Naomi E.; Oellerich, Thomas; Urlaub, Henning; Engelke, Michael; Wienands, Jürgen; Bruckbauer, Andreas; Batista, Facundo D.

doi:10.1016/j.immuni.2011.06.001

Cited by 88 publications

(110 citation statements)

References 55 publications

Supporting

Mentioning

102

Contrasting

Order By: Relevance

“…Early studies of ours and others showed that signaling-active BCR microclusters were usually well colocalized with membraneproximal signaling microclusters, such as pSyk and pTyr microclusters (4,15,16,33). We thus compared the spatial distribution of BCR microclusters to either pSyk or pTyr microclusters induced by Ags tethered to substrates with high or low stiffness using Pearson correlation index analysis as reported previously (4).…”

Section: Resultsmentioning

confidence: 91%

“…Recent live cell imaging studies by other laboratories, as well as our own, showed that the formation of BCR microclusters and the B cell immunological synapse are two key early events in the initiation of B cell activation (1,4,5,13). Subsequent studies demonstrated that reorganization of the B cell cytoskeleton provides indispensable support for both of these events in the process of B cell activation by maintaining the dynamic growth feature of BCR microclusters and the coalescence of BCR microclusters and signaling molecule microclusters (4,(14)(15)(16). Moreover, the centripetal movements of BCR microclusters to the center of the B cell immunological synapse are shown to depend on the coordination of the cytoskeleton, motor proteins, and BCR signaling molecules (15).…”

mentioning

confidence: 92%

“…Subsequent studies demonstrated that reorganization of the B cell cytoskeleton provides indispensable support for both of these events in the process of B cell activation by maintaining the dynamic growth feature of BCR microclusters and the coalescence of BCR microclusters and signaling molecule microclusters (4,(14)(15)(16). Moreover, the centripetal movements of BCR microclusters to the center of the B cell immunological synapse are shown to depend on the coordination of the cytoskeleton, motor proteins, and BCR signaling molecules (15). Interestingly, the membrane cytoskeleton and motor proteins have been shown to be key players in regulating cell mechanics and morphology changes (17)(18)(19).…”

mentioning

confidence: 99%

See 2 more Smart Citations

B Cell Activation Is Regulated by the Stiffness Properties of the Substrate Presenting the Antigens

Wan

Zhang

Fan

et al. 2013

The Journal of Immunology

104

View full text Add to dashboard Cite

B lymphocytes are activated upon Ag sensing by BCRs. The substrate presenting the Ag can show different degrees of stiffness. It is not clear whether B cells can respond to changes in substrate stiffness. In this study we use high-resolution, high-speed live cell imaging techniques to capture the molecular events in B cell activation after the recognition of Ags tethered to polyacrylamide gel substrates with variable degrees of stiffness as quantified by Young’s modulus (2.6–22.1 kPa). We show that the initiation of B cell activation is extremely sensitive to substrate stiffness. B cells exhibit much stronger activation responses when encountering Ags tethered to substrates with a high degree of stiffness as measured by the accumulation of BCR, phospho-spleen tyrosine kinase, and phosphotyrosine molecules into the B cell immunological synapse. Ags tethered to stiff substrates induce the formation of more prominent BCR and phospho-spleen tyrosine kinase microclusters with significantly enhanced colocalization as compared with Ags tethered to soft substrates. Moreover, the expression of the B cell activation marker CD69 is enhanced in B cells encountering Ags on stiffer substrates. Through time-lapse live cell imaging, we find that the different responses of B cells to substrate stiffness are only demonstrated 5 min after BCR and Ag recognition. Using a series of cytoskeleton inhibitors, we determine that the mechanosensing ability of B cells is dependent on microtubules, and only mildly linked to the actin cytoskeleton. These results suggest the importance of the mechanical properties mediated by substrate stiffness in B cell activation.

show abstract

Section: Resultsmentioning

confidence: 91%

mentioning

confidence: 92%

mentioning

confidence: 99%

See 1 more Smart Citation

B Cell Activation Is Regulated by the Stiffness Properties of the Substrate Presenting the Antigens

Wan

Zhang

Fan

et al. 2013

The Journal of Immunology

104

View full text Add to dashboard Cite

show abstract

“…A similar dependence on diffusion was found for the inhibitory capacity of In addition, BCR microclusters interact with microtubules via the cytoskeletal motor protein dynein, which contributes to the compaction of antigen clusters in the center of the synapse and to the reorientation of the microtubule-organizing center (MTOC) towards the synapse 120,121 .…”

Section: [H1] Cytoskeletal Regulation Of Bcr Signallingmentioning

confidence: 53%

Cytoskeletal control of B cell responses to antigens

Tolar

2017

Nat Rev Immunol

118

View full text Add to dashboard Cite

The actin cytoskeleton is essential for cell mechanics and has increasingly been implicated in the regulation of cell signalling. In B cells, the actin cytoskeleton couples extensively to B cell receptor (BCR) signalling pathways and its defects can either enhance or suppress B cell activation. Recent insights from single-cell imaging and biophysical techniques suggest that actin orchestrates BCR signalling at the plasma membrane through effects on protein diffusion, and that it regulates antigen discrimination through the biomechanics of immune synapses. These mechanical functions also play a role in the adaptation of B cell subsets to specialized tasks during antibody responses.3

show abstract

“…Concomitant actin polymerization at the cell periphery allows the B cell to spread across the antigen-bearing surface, encounter more antigens, and form additional BCR microclusters (Fleire et al, 2006;Song et al, 2013). Subsequent contraction of the B cell membrane (Fleire et al, 2006) is accompanied by microtubule-dependent gathering of BCR microclusters into a central supramolecular activation cluster (cSMAC) (Schnyder et al, 2011) that is characteristic of an immune synapse (IS) (Dustin et al, 2010). At the IS, B cells extract BCRbound antigens from APCs (Batista et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

The Rap1–cofilin-1 pathway coordinates actin reorganization and MTOC polarization at the B cell immune synapse

Wang

Lee

Christian

et al. 2017

Journal of Cell Science

View full text Add to dashboard Cite

B cells that bind antigens displayed on antigen-presenting cells (APCs) form an immune synapse, a polarized cellular structure that optimizes the dual functions of the B cell receptor (BCR), signal transduction and antigen internalization. Immune synapse formation involves polarization of the microtubule-organizing center (MTOC) towards the APC. We now show that BCR-induced MTOC polarization requires the Rap1 GTPase (which has two isoforms, Rap1a and Rap1b), an evolutionarily conserved regulator of cell polarity, as well as cofilin-1, an actin-severing protein that is regulated by Rap1. MTOC reorientation towards the antigen contact site correlated strongly with cofilin-1-dependent actin reorganization and cell spreading. We also show that BCR-induced MTOC polarization requires the dynein motor protein as well as IQGAP1, a scaffolding protein that can link the actin and microtubule cytoskeletons. At the periphery of the immune synapse, IQGAP1 associates closely with Factin structures and with the microtubule plus-end-binding protein CLIP-170 (also known as CLIP1). Moreover, the accumulation of IQGAP1 at the antigen contact site depends on F-actin reorganization that is controlled by Rap1 and cofilin-1. Thus the Rap1-cofilin-1 pathway coordinates actin and microtubule organization at the immune synapse.

show abstract

B Cell Receptor-Mediated Antigen Gathering Requires Ubiquitin Ligase Cbl and Adaptors Grb2 and Dok-3 to Recruit Dynein to the Signaling Microcluster

Cited by 88 publications

References 55 publications

B Cell Activation Is Regulated by the Stiffness Properties of the Substrate Presenting the Antigens

B Cell Activation Is Regulated by the Stiffness Properties of the Substrate Presenting the Antigens

Cytoskeletal control of B cell responses to antigens

The Rap1–cofilin-1 pathway coordinates actin reorganization and MTOC polarization at the B cell immune synapse

Contact Info

Product

Resources

About