Cofilin-Mediated F-Actin Severing Is Regulated by the Rap GTPase and Controls the Cytoskeletal Dynamics That Drive Lymphocyte Spreading and BCR Microcluster Formation

Freeman, Spencer A.; Lei, Victor; Dang-Lawson, May; Mizuno, Kensaku; Roskelley, Calvin D.; Gold, Michael R.

doi:10.4049/jimmunol.1102233

Cited by 93 publications

(161 citation statements)

References 39 publications

(60 reference statements)

Supporting

Mentioning

157

Contrasting

Order By: Relevance

“…Antigens that are immobilized onto beads or planar coverslips, embedded in planar lipid bilayers or expressed on the surface of APCs have been used to create a polarized antigen contact site in order to model events that occur at the IS (Fleire et al, 2006;Freeman et al, 2011;Lin et al, 2008;Reversat et al, 2015;Yuseff et al, 2011). In all cases, B cells initially extend their plasma membrane across the antigen-coated surface (Fig.…”

Section: Bcr-induced Mtoc Polarization Depends On Rap1mentioning

confidence: 99%

“…S1A-C). This requires Rap1-dependent reorganization of the actin cytoskeleton (Freeman et al, 2011;Lin et al, 2008).…”

Section: Bcr-induced Mtoc Polarization Depends On Rap1mentioning

confidence: 99%

“…For membraneassociated antigens, BCR-induced reorganization of the actin and microtubule cytoskeletons is critical for the two functions of the BCR, signal transduction and antigen internalization Song et al, 2013;Yuseff et al, 2013). Initial BCR signaling at the B-cell-APC interface promotes disassembly of the submembrane actin network and uncouples the actin meshwork from the plasma membrane (Freeman et al, 2011;Treanor et al, 2011Treanor et al, , 2010. This increases BCR mobility (Freeman et al, 2015;Treanor et al, 2010), allowing antigen-bound BCRs to form microclusters that recruit signaling enzymes Tolar et al, 2009;Treanor et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…The Rap1 GTPase (which has two isoforms, Rap1a and Rap1b) controls actin dynamics and organization (Freeman et al, 2011) and is important for establishing cell polarity. Bud1p (also known as Rsr1p), the yeast ortholog of Rap1, controls bud site selection and establishes cell polarity by acting upstream of Cdc42 to initiate polarized actin polymerization and promoting reorientation of microtubules towards the bud site (Chant, 1999;Etienne-Manneville, 2004;Kang et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…In B cells, Rap1 is activated by the BCR (McLeod et al, 1998) and the active GTP-bound form of Rap1 accumulates at the contact site with particulate antigens (Lin et al, 2008). BCRinduced Rap1 activation is also required for actin reorganization at the IS (Freeman et al, 2011;Lin et al, 2008). We now show that Rap1 coordinates actin remodeling and MTOC polarization at the B cell IS and that this involves the actin-severing protein cofilin-1 (hereafter referred to as cofilin), which we previously showed is a downstream target of Rap1 (Freeman et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

Self Cite

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

Section: Bcr-induced Mtoc Polarization Depends On Rap1mentioning

confidence: 99%

“…S1A-C). This requires Rap1-dependent reorganization of the actin cytoskeleton (Freeman et al, 2011;Lin et al, 2008).…”

Section: Bcr-induced Mtoc Polarization Depends On Rap1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

show abstract

Involvement of MST1/mTORC1/STAT1 activity in the regulation of B‐cell receptor signalling by chemokine receptor 2

Zhu

Lü

et al. 2022

Clinical & Translational Med

View full text Add to dashboard Cite

Background CCR2 is involved in maintaining immune homeostasis and regulating immune function. This study aims to elucidate the mechanism by which CCR2 regulates B‐cell signalling. Methods In Ccr2 ‐knockout mice, the development and differentiation of B cells, BCR proximal signals, actin movement and B‐cell immune response were determined. Besides, the level of CCR2 in PBMC of SLE patients was analysed by bioinformatics. Results CCR2 deficiency reduces the proportion and number of follicular B cells, upregulates BCR proximal signalling and enhances the oxidative phosphorylation of B cells. Meanwhile, increased actin filaments aggregation and its associated early‐activation events of B cells are also induced by CCR2 deficiency. The MST1/mTORC1/STAT1 axis in B cells is responsible for the regulation of actin remodelling, metabolic activities and transcriptional signalling, specific MST1, mTORC1 or STAT1 inhibitor can rescue the upregulated BCR signalling. Glomerular IgG deposition is obvious in CCR2‐deficient mice, accompanied by increased anti‐dsDNA IgG level. Additionally, the CCR2 expression in peripheral B cells of SLE patients is decreased than that of healthy controls. Conclusions CCR2 can utilise MST1/mTORC1/STAT1 axis to regulate BCR signalling. The interaction between CCR2 and BCR may contribute to exploring the mechanism of autoimmune diseases.

show abstract

Swiprosin‐1/EFhd2 limits germinal center responses and humoral type 2 immunity

et al. 2014

View full text Add to dashboard Cite

Activated B cells are selected for in germinal centers by regulation of their apoptosis.The Ca 2+ -binding cytoskeletal adaptor protein Swiprosin-1/EFhd2 (EFhd2) can promote apoptosis in activated B cells. We therefore hypothesized that EFhd2 might limit humoral immunity by repressing both the germinal center reaction and the expected enhancement of immune responses in the absence of EFhd2. Here, we established EFhd2 −/− mice on a C57BL/6 background, which revealed normal B-and T-cell development, basal Ab levels, and T-cell independent type 1, and T-cell independent type 2 responses. However, T cell-dependent immunization with sheep red blood cells and infection with the helminth Nippostrongylus brasiliensis (N.b) increased production of antibodies of multiple isotypes, as well as germinal center formation in EFhd2 −/− mice. In addition, serum IgE levels and numbers of IgE + plasma cells were strongly increased in EFhd2 −/− mice, both after primary as well as after secondary N.b infection. Finally, mixed bone marrow chimeras unraveled an EFhd2-dependent B cell-intrinsic contribution to increased IgE plasma cell numbers in N.b-infected mice. Hence, we established a role for EFhd2 as a negative regulator of germinal center-dependent humoral type 2 immunity, with implications for the generation of IgE. Keywords:Germinal center r IgE r Nippostrongylus brasiliensis r Plasma cell r Swiprosin-1/ EFhd2Additional supporting information may be found in the online version of this article at the publisher's web-site [11]. These short-lived plasma cells provide an initial wave of mostly non class-switched low affinity antibodies. Second, the early activated B cells can form GC where Ab affinity maturation takes place [12,13]. GC B cells upregulate activation induced deaminase (AID), and start to hypermutate the V exons of their Ig genes in the dark zone of the GC [10]. Later, these B cells migrate to the light zone of the GC, where they differentiate into centrocytes. There, they become negatively selected by default through apoptosis but can be rescued by antigen presentation to follicular T helper cells (T FH ) to receive essential survival signals [14]. Those survival signals are usually reserved for high affine, non autoreactive B cells. Centrocytes can leave the GC to develop into long-lived, class-switched and affinity-matured plasma cells that home back to the BM, resulting in sustained production of high-affinity antibodies [15], but to what extent IgE-expressing plasma cells participate in this step is being controversially discussed [16][17][18][19][20].The mechanism of the maturation of IgE-positive B cells is of considerable interest with respect to type I hypersensitivity reactions that can have life-threatening anaphylactic outcomes. Maturation of IgE-positive B cells involves a GC-dependent CSR pathway [16,17] but there is also evidence for indirect CSR to IgE by switching to IgG1 through an initial GC reaction, followed by an extrafollicular maturation phase and switching to IgE [19,20]. It is agreed upon t...

show abstract

Cofilin-Mediated F-Actin Severing Is Regulated by the Rap GTPase and Controls the Cytoskeletal Dynamics That Drive Lymphocyte Spreading and BCR Microcluster Formation

Cited by 93 publications

References 39 publications

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

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

Involvement of MST1/mTORC1/STAT1 activity in the regulation of B‐cell receptor signalling by chemokine receptor 2

Swiprosin‐1/EFhd2 limits germinal center responses and humoral type 2 immunity

Contact Info

Product

Resources

About