The actin cytoskeleton coordinates the signal transduction and antigen processing functions of the B cell antigen receptor

Abstract

The B cell antigen receptor (BCR) is the sensor on the B cell surface that surveys foreign molecules (antigen) in our bodies and activates B cells to generate antibody responses upon encountering cognate antigen. The binding of antigen to the BCR induces signaling cascades in the cytoplasm, which provides the first signal for B cell activation. Subsequently, BCRs internalize and target bound antigen to endosomes, where antigen is processed into T cell recognizable forms. T helper cells generate the second activation signal upon binding to antigen presented by B cells. The optimal activation of B cells requires both signals, thereby depending on the coordination of BCR signaling and antigen transport functions. Antigen binding to the BCR also induces rapid remodeling of the cortical actin network of B cells. While being initiated and controlled by BCR signaling, recent studies reveal that this actin remodeling is critical for both the signaling and antigen processing functions of the BCR, indicating a role for actin in coordinating these two pathways. Here we will review previous and recent studies on actin reorganization during BCR activation and BCR-mediated antigen processing, and discuss how actin remodeling translates BCR signaling into rapid antigen uptake and processing while providing positive and negative feedback to BCR signaling.

Keywords

actin cytoskeleton / endocytosis / signal transduction / receptor

References

[1] Ahmed S (2011). Nanoscopy of cell architecture: The actin-membrane interface. BioArchitecture, 1(1): 32–38

[2] Amann K J, Pollard T D (2001). The Arp2/3 complex nucleates actin filament branches from the sides of pre-existing filaments. Nat Cell Biol, 3(3): 306–310

[3] Baba Y, Hashimoto S, Matsushita M, Watanabe D, Kishimoto T, Kurosaki T, Tsukada S (2001). BLNK mediates Syk-dependent Btk activation. Proc Natl Acad Sci USA, 98(5): 2582–2586

[4] Bachvaroff R J, Miller F, Rapaport F T (1980). Appearance of cytoskeletal components on the surface of leukemia cells and of lymphocytes transformed by mitogens and Epstein-Barr virus. Proc Natl Acad Sci USA, 77(8): 4979–4983

[5] Bassing C H, Swat W, Alt F W (2002). The mechanism and regulation of chromosomal V(D)J recombination. Cell, 109(2 Suppl): S45–S55

[6] Bernstein B W, Bamburg J R (2010). ADF/cofilin: a functional node in cell biology. Trends Cell Biol, 20(4): 187–195

[7] Blundell M P, Bouma G, Metelo J, Worth A, Calle Y, Cowell L A, Westerberg L S, Moulding D A, Mirando S, Kinnon C, Cory G O, Jones G E, Snapper S B, Burns S O, Thrasher A J (2009). Phosphorylation of WASp is a key regulator of activity and stability in vivo. Proc Natl Acad Sci USA, 106(37): 15738–15743

[8] Boes M, Cuvillier A, Ploegh H (2004). Membrane specializations and endosome maturation in dendritic cells and B cells. Trends Cell Biol, 14(4): 175–183

[9] Bolland S, Pearse R N, Kurosaki T, Ravetch J V (1998). SHIP modulates immune receptor responses by regulating membrane association of Btk. Immunity, 8(4): 509–516

[10] Braun J, Fujiwara K, Pollard T D, Unanue E R (1978). Two distinct mechanisms for redistribution of lymphocyte surface macromolecules. I. Relationship to cytoplasmic myosin. J Cell Biol, 79(2 Pt 1): 409–418

[11] Braun J, Hochman P S, Unanue E R (1982). Ligand-induced association of surface immunoglobulin with the detergent-insoluble cytoskeletal matrix of the B lymphocyte. J Immunol, 128(3): 1198–1204

[12] Brauweiler A M, Cambier J C (2003). Fc gamma RIIB activation leads to inhibition of signalling by independently ligated receptors. Biochem Soc Trans, 31(Pt 1): 281–285

[13] Brezski R J, Monroe J G (2008). B-cell receptor. Adv Exp Med Biol, 640: 12–21

[14] Brown B K, Song W (2001). The actin cytoskeleton is required for the trafficking of the B cell antigen receptor to the late endosomes. Traffic, 2(6): 414–427

[15] Carpenter C L (2004). Btk-dependent regulation of phosphoinositide synthesis. Biochem Soc Trans, 32(Pt 2): 326–329

[16] Carrasco Y R, Fleire S J, Cameron T, Dustin M L, Batista F D (2004). LFA-1/ICAM-1 interaction lowers the threshold of B cell activation by facilitating B cell adhesion and synapse formation. Immunity, 20(5): 589–599

[17] Casten L A, Kaumaya P, Pierce S K (1988). Enhanced T cell responses to antigenic peptides targeted to B cell surface Ig, Ia, or class I molecules. J Exp Med, 168(1): 171–180

[18] Collins A, Warrington A, Taylor K A, Svitkina T (2011). Structural organization of the actin cytoskeleton at sites of clathrin-mediated endocytosis. Curr Biol, 21(14): 1167–1175

[19] Cory G O, Cramer R, Blanchoin L, Ridley A J (2003). Phosphorylation of the WASP-VCA domain increases its affinity for the Arp2/3 complex and enhances actin polymerization by WASP. Mol Cell, 11(5): 1229–1239

[20] Cory G O, Garg R, Cramer R, Ridley A J (2002). Phosphorylation of tyrosine 291 enhances the ability of WASp to stimulate actin polymerization and filopodium formation. Wiskott-Aldrich Syndrome protein. J Biol Chem, 277(47): 45115–45121

[21] Dal Porto J M, Gauld S B, Merrell K T, Mills D, Pugh-Bernard A E, Cambier J (2004). B cell antigen receptor signaling 101. Mol Immunol, 41(6-7): 599–613

[22] Depoil D, Fleire S, Treanor B L, Weber M, Harwood N E, Marchbank K L, Tybulewicz V L, Batista F D (2008). CD19 is essential for B cell activation by promoting B cell receptor-antigen microcluster formation in response to membrane-bound ligand. Nat Immunol, 9(1): 63–72

[23] Dustin M L (2008). T-cell activation through immunological synapses and kinapses. Immunol Rev, 221(1): 77–89

[24] Engels N, König L M, Heemann C, Lutz J, Tsubata T, Griep S, Schrader V, Wienands J (2009). Recruitment of the cytoplasmic adaptor Grb2 to surface IgG and IgE provides antigen receptor-intrinsic costimulation to class-switched B cells. Nat Immunol, 10(9): 1018–1025

[25] Etienne-Manneville S (2004). Cdc42—the centre of polarity. J Cell Sci, 117(Pt 8): 1291–1300

[26] Fehon R G, McClatchey A I, Bretscher A (2010). Organizing the cell cortex: the role of ERM proteins. Nat Rev Mol Cell Biol, 11(4): 276–287

[27] Fievet B T, Gautreau A, Roy C, Del Maestro L, Mangeat P, Louvard D, Arpin M (2004). Phosphoinositide binding and phosphorylation act sequentially in the activation mechanism of ezrin. J Cell Biol, 164(5): 653–659

[28] Finkelstein L D, Schwartzberg P L (2004). Tec kinases: shaping T-cell activation through actin. Trends Cell Biol, 14(8): 443–451

[29] Firat-Karalar E N, Welch M D (2011). New mechanisms and functions of actin nucleation. Curr Opin Cell Biol, 23(1): 4–13

[30] Fleire S J, Goldman J P, Carrasco Y R, Weber M, Bray D, Batista F D (2006). B cell ligand discrimination through a spreading and contraction response. Science, 312(5774): 738–741

[31] Freeman S A, Lei V, Dang-Lawson M, Mizuno K, Roskelley C D, Gold M R (2011). Cofilin-mediated F-actin severing is regulated by the Rap GTPase and controls the cytoskeletal dynamics that drive lymphocyte spreading and BCR microcluster formation. J Immunol, 187(11): 5887–5900

[32] Fujimoto M, Poe J C, Satterthwaite A B, Wahl M I, Witte O N, Tedder T F (2002). Complementary roles for CD19 and Bruton’s tyrosine kinase in B lymphocyte signal transduction. J Immunol, 168(11): 5465–5476

[33] Galletta B J, Mooren O L, Cooper J A (2010). Actin dynamics and endocytosis in yeast and mammals. Curr Opin Biotechnol, 21(5): 604–610

[34] Gonzalez S F, Degn S E, Pitcher L A, Woodruff M, Heesters B A, Carroll M C (2011). Trafficking of B cell antigen in lymph nodes. Annu Rev Immunol, 29(1): 215–233

[35] Gonzalez S F, Pitcher L A, Mempel T, Schuerpf F, Carroll M C (2009). B cell acquisition of antigen in vivo. Curr Opin Immunol, 21(3): 251–257

[36] Guagliardi L E, Koppelman B, Blum J S, Marks M S, Cresswell P, Brodsky F M (1990). Co-localization of molecules involved in antigen processing and presentation in an early endocytic compartment. Nature, 343(6254): 133–139

[37] Gupta N, Wollscheid B, Watts J D, Scheer B, Aebersold R, DeFranco A L (2006). Quantitative proteomic analysis of B cell lipid rafts reveals that ezrin regulates antigen receptor-mediated lipid raft dynamics. Nat Immunol, 7(6): 625–633

[38] Harder T, Scheiffele P, Verkade P, Simons K (1998). Lipid domain structure of the plasma membrane revealed by patching of membrane components. J Cell Biol, 141(4): 929–942

[39] Hartwig J H, Jugloff L S, De Groot N J, Grupp S A, Jongstra-Bilen J (1995). The ligand-induced membrane IgM association with the cytoskeletal matrix of B cells is not mediated through the Ig alpha beta heterodimer. J Immunol, 155(8): 3769–3779

[40] Harwood N E, Batista F D (2009). Visualizing the molecular and cellular events underlying the initiation of B-cell activation. Curr Top Microbiol Immunol, 334: 153–177

[41] Harwood N E, Batista F D (2010). Early events in B cell activation. Annu Rev Immunol, 28(1): 185–210

[42] Ilani T, Vasiliver-Shamis G, Vardhana S, Bretscher A, Dustin M L (2009). T cell antigen receptor signaling and immunological synapse stability require myosin IIA. Nat Immunol, 10(5): 531–539

[43] Jugloff L S, Jongstra-Bilen J (1997). Cross-linking of the IgM receptor induces rapid translocation of IgM-associated Ig alpha, Lyn, and Syk tyrosine kinases to the membrane skeleton. J Immunol, 159(3): 1096–1106

[44] Kumari S, Vardhana S, Cammer M, Curado S, Santos L, Sheetz M P, Dustin M L (2012). T Lymphocyte Myosin IIA is Required for Maturation of the Immunological Synapse. Front Immunol, 3: 230

[45] Kurosaki T (2011). Regulation of BCR signaling. Mol Immunol, 48(11): 1287–1291

[46] Kusumi A, Fujiwara T K, Chadda R, Xie M, Tsunoyama T A, Kalay Z, Kasai R S, Suzuki K G (2012a). Dynamic organizing principles of the plasma membrane that regulate signal transduction: commemorating the fortieth anniversary of Singer and Nicolson’s fluid-mosaic model. Annu Rev Cell Dev Biol, 28(1): 215–250

[47] Kusumi A, Fujiwara T K, Morone N, Yoshida K J, Chadda R, Xie M, Kasai R S, Suzuki K G (2012b). Membrane mechanisms for signal transduction: the coupling of the meso-scale raft domains to membrane-skeleton-induced compartments and dynamic protein complexes. Semin Cell Dev Biol, 23(2): 126–144

[48] Labno C M, Lewis C M, You D, Leung D W, Takesono A, Kamberos N, Seth A, Finkelstein L D, Rosen M K, Schwartzberg P L, Burkhardt J K (2003). Itk functions to control actin polymerization at the immune synapse through localized activation of Cdc42 and WASP. Curr Biol, 13(18): 1619–1624

[49] Larbolette O, Wollscheid B, Schweikert J, Nielsen P J, Wienands J (1999). SH3P7 is a cytoskeleton adapter protein and is coupled to signal transduction from lymphocyte antigen receptors. Mol Cell Biol, 19(2): 1539–1546

[50] Liu C, Miller H, Hui K L, Grooman B, Bolland S, Upadhyaya A, Song W (2011). A balance of Bruton’s tyrosine kinase and SHIP activation regulates B cell receptor cluster formation by controlling actin remodeling. J Immunol, 187(1): 230–239

[51] Liu C, Miller H, Orlowski G, Hang H, Upadhyaya A, Song W (2012a). Actin reorganization is required for the formation of polarized B cell receptor signalosomes in response to both soluble and membrane-associated antigens. J Immunol, 188(7): 3237–3246

[52] Liu C, Miller H, Sharma S, Beaven A, Upadhyaya A, Song W (2012b). Analyzing actin dynamics during the activation of the B cell receptor in live B cells. Biochem Biophys Res Commun, 427(1): 202–206

[53] Liu W, Meckel T, Tolar P, Sohn H W, Pierce S K (2010a). Antigen affinity discrimination is an intrinsic function of the B cell receptor. J Exp Med, 207(5): 1095–1111

[54] Liu W, Meckel T, Tolar P, Sohn H W, Pierce S K (2010b). Intrinsic properties of immunoglobulin IgG1 isotype-switched B cell receptors promote microclustering and the initiation of signaling. Immunity, 32(6): 778–789

[55] Liu W, Won Sohn H, Tolar P, Meckel T, Pierce S K (2010c). Antigen-induced oligomerization of the B cell receptor is an early target of Fc gamma RIIB inhibition. J Immunol, 184(4): 1977–1989

[56] Malhotra S, Kovats S, Zhang W, Coggeshall K M (2009a). B cell antigen receptor endocytosis and antigen presentation to T cells require Vav and dynamin. J Biol Chem, 284(36): 24088–24097

[57] Malhotra S, Kovats S, Zhang W, Coggeshall K M (2009b). Vav and Rac activation in B cell antigen receptor endocytosis involves Vav recruitment to the adapter protein LAB. J Biol Chem, 284(52): 36202–36212

[58] Mongini P K, Blessinger C A, Highet P F, Inman J K (1992). Membrane IgM-mediated signaling of human B cells. Effect of increased ligand binding site valency on the affinity and concentration requirements for inducing diverse stages of activation. J Immunol, 148(12): 3892–3901

[59] Mooren O L, Galletta B J, Cooper J A (2012). Roles for actin assembly in endocytosis. Annu Rev Biochem, 81(1): 661–686

[60] Natkanski E, Lee W Y, Mistry B, Casal A, Molloy J E, Tolar P (2013). B Cells Use Mechanical Energy to Discriminate Antigen Affinities. Science, 340(6140): 1587–1590

[61] Neisch A L, Fehon R G (2011). Ezrin, Radixin and Moesin: key regulators of membrane-cortex interactions and signaling. Curr Opin Cell Biol, 23(4): 377–382

[62] Niiro H, Clark E A (2002). Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol, 2(12): 945–956

[63] O’Neill S K, Getahun A, Gauld S B, Merrell K T, Tamir I, Smith M J, Dal Porto J M, Li Q Z, Cambier J C (2011). Monophosphorylation of CD79a and CD79b ITAM motifs initiates a SHIP-1 phosphatase-mediated inhibitory signaling cascade required for B cell anergy. Immunity, 35(5): 746–756

[64] Oltz E M (2001). Regulation of antigen receptor gene assembly in lymphocytes. Immunol Res, 23(2-3): 121–133

[65] Onabajo O O, Seeley M K, Kale A, Qualmann B, Kessels M, Han J, Tan T H, Song W (2008). Actin-binding protein 1 regulates B cell receptor-mediated antigen processing and presentation in response to B cell receptor activation. J Immunol, 180(10): 6685–6695

[66] Padrick S B, Rosen M K (2010). Physical mechanisms of signal integration by WASP family proteins. Annu Rev Biochem, 79(1): 707–735

[67] Park J Y, Jongstra-Bilen J (1997). Interactions between membrane IgM and the cytoskeleton involve the cytoplasmic domain of the immunoglobulin receptor. Eur J Immunol, 27(11): 3001–3009

[68] Pollard T D, Cooper J A (2009). Actin, a central player in cell shape and movement. Science, 326(5957): 1208–1212

[69] Puré E, Tardelli L (1992). Tyrosine phosphorylation is required for ligand-induced internalization of the antigen receptor on B lymphocytes. Proc Natl Acad Sci USA, 89(1): 114–117

[70] Reth M (1992). Antigen receptors on B lymphocytes. Annu Rev Immunol, 10(1): 97–121

[71] Ridley A J (2011). Life at the leading edge. Cell, 145(7): 1012–1022

[72] Saito K, Tolias K F, Saci A, Koon H B, Humphries L A, Scharenberg A, Rawlings D J, Kinet J P, Carpenter C L (2003). BTK regulates PtdIns-4,5-P2 synthesis: importance for calcium signaling and PI3K activity. Immunity, 19(5): 669–678

[73] Schreiner G F, Fujiwara K, Pollard T D, Unanue E R (1977). Redistribution of myosin accompanying capping of surface Ig. J Exp Med, 145(5): 1393–1398

[74] Schreiner G F, Unanue E R (1977). Capping and the lymphocyte: models for membrane reorganization. J Immunol, 119(5): 1549–1551

[75] Sharma S, Orlowski G, Song W (2009). Btk regulates B cell receptor-mediated antigen processing and presentation by controlling actin cytoskeleton dynamics in B cells. J Immunol, 182(1): 329–339

[76] Siemasko K, Clark M R (2001). The control and facilitation of MHC class II antigen processing by the BCR. Curr Opin Immunol, 13(1): 32–36

[77] Simons P C, Pietromonaco S F, Reczek D, Bretscher A, Elias L (1998). C-terminal threonine phosphorylation activates ERM proteins to link the cell’s cortical lipid bilayer to the cytoskeleton. Biochem Biophys Res Commun, 253(3): 561–565

[78] Sohn H W, Tolar P, Jin T, Pierce S K (2006). Fluorescence resonance energy transfer in living cells reveals dynamic membrane changes in the initiation of B cell signaling. Proc Natl Acad Sci USA, 103(21): 8143–8148

[79] Sohn H W, Tolar P, Pierce S K (2008). Membrane heterogeneities in the formation of B cell receptor-Lyn kinase microclusters and the immune synapse. J Cell Biol, 182(2): 367–379

[80] Song W, Cho H, Cheng P, Pierce S K (1995). Entry of B cell antigen receptor and antigen into class II peptide-loading compartment is independent of receptor cross-linking. J Immunol, 155(9): 4255–4263

[81] Stoddart A, Dykstra M L, Brown B K, Song W, Pierce S K, Brodsky F M (2002). Lipid rafts unite signaling cascades with clathrin to regulate BCR internalization. Immunity, 17(4): 451–462

[82] Stoddart A, Jackson A P, Brodsky F M (2005). Plasticity of B cell receptor internalization upon conditional depletion of clathrin. Mol Biol Cell, 16(5): 2339–2348

[83] Stradal T E, Scita G (2006). Protein complexes regulating Arp2/3-mediated actin assembly. Curr Opin Cell Biol, 18(1): 4–10

[84] Thrasher A J, Burns S O (2010). WASP: a key immunological multitasker. Nat Rev Immunol, 10(3): 182–192

[85] Tolar P, Hanna J, Krueger P D, Pierce S K (2009a). The constant region of the membrane immunoglobulin mediates B cell-receptor clustering and signaling in response to membrane antigens. Immunity, 30(1): 44–55

[86] Tolar P, Sohn H W, Liu W, Pierce S K (2009b). The molecular assembly and organization of signaling active B-cell receptor oligomers. Immunol Rev, 232(1): 34–41

[87] Tolar P, Sohn H W, Pierce S K (2005). The initiation of antigen-induced B cell antigen receptor signaling viewed in living cells by fluorescence resonance energy transfer. Nat Immunol, 6(11): 1168–1176

[88] Tolar P, Sohn H W, Pierce S K (2008). Viewing the antigen-induced initiation of B-cell activation in living cells. Immunol Rev, 221(1): 64–76

[89] Treanor B, Depoil D, Bruckbauer A, Batista F D (2011). Dynamic cortical actin remodeling by ERM proteins controls BCR microcluster organization and integrity. J Exp Med, 208(5): 1055–1068

[90] Treanor B, Depoil D, Gonzalez-Granja A, Barral P, Weber M, Dushek O, Bruckbauer A, Batista F D (2010). The membrane skeleton controls diffusion dynamics and signaling through the B cell receptor. Immunity, 32(2): 187–199

[91] Unanue E R, Perkins W D, Karnovsky M J (1972). Ligand-induced movement of lymphocyte membrane macromolecules. I. Analysis by immunofluorescence and ultrastructural radioautography. J Exp Med, 136(4): 885–906

[92] Van Troys M, Huyck L, Leyman S, Dhaese S, Vandekerkhove J, Ampe C (2008). Ins and outs of ADF/cofilin activity and regulation. Eur J Cell Biol, 87(8-9): 649–667

[93] Vascotto F, Le Roux D, Lankar D, Faure-André G, Vargas P, Guermonprez P, Lennon-Duménil A M (2007). Antigen presentation by B lymphocytes: how receptor signaling directs membrane trafficking. Curr Opin Immunol, 19(1): 93–98

[94] Vicente-Manzanares M, Ma X, Adelstein R S, Horwitz A R (2009). Non-muscle myosin II takes centre stage in cell adhesion and migration. Nat Rev Mol Cell Biol, 10(11): 778–790

[95] Weber M, Treanor B, Depoil D, Shinohara H, Harwood N E, Hikida M, Kurosaki T, Batista F D (2008). Phospholipase C-gamma2 and Vav cooperate within signaling microclusters to propagate B cell spreading in response to membrane-bound antigen. J Exp Med, 205(4): 853–868

[96] Yang N, Higuchi O, Ohashi K, Nagata K, Wada A, Kangawa K, Nishida E, Mizuno K (1998). Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature, 393(6687): 809–812

[97] Yokoyama N, Lougheed J, Miller W T (2005). Phosphorylation of WASP by the Cdc42-associated kinase ACK1: dual hydroxyamino acid specificity in a tyrosine kinase. J Biol Chem, 280(51): 42219–42226

[98] Yuseff M I, Reversat A, Lankar D, Diaz J, Fanget I, Pierobon P, Randrian V, Larochette N, Vascotto F, Desdouets C, Jauffred B, Bellaiche Y, Gasman S, Darchen F, Desnos C, Lennon-Duménil A M (2011). Polarized secretion of lysosomes at the B cell synapse couples antigen extraction to processing and presentation. Immunity, 35(3): 361–374

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