title: Wiskott-Aldrich Syndrome Interacting Protein Deficiency Uncovers the Role of the Co-receptor CD19 as a Generic Hub for PI3 Kinase Signaling in B Cells.
abstract: Humans with Wiskott-Aldrich syndrome display a progressive immunological disorder associated with compromised Wiskott-Aldrich Syndrome Interacting Protein (WIP) function. Mice deficient in WIP recapitulate such an immunodeficiency that has been attributed to T cell dysfunction; however, any contribution of B cells is as yet undefined. Here we have shown that WIP deficiency resulted in defects in B cell homing, chemotaxis, survival, and differentiation, ultimately leading to diminished germinal center formation and antibody production. Furthermore, in the absence of WIP, several receptors, namely the BCR, BAFFR, CXCR4, CXCR5, CD40, and TLR4, were impaired in promoting CD19 co-receptor activation and subsequent PI3 kinase (PI3K) signaling. The underlying mechanism was due to a distortion in the actin and tetraspanin networks that lead to altered CD19 cell surface dynamics. In conclusion, our findings suggest that, by regulating the cortical actin cytoskeleton, WIP influences the function of CD19 as a general hub for PI3K signaling.
authors.affiliation: Lymphocyte Interaction Laboratory, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Selina Jessica
authors.initials: SJ
authors.lastname: Keppler
authors.affiliation: Lymphocyte Interaction Laboratory, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Gasparrini
authors.affiliation: Lymphocyte Interaction Laboratory, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Marianne
authors.initials: M
authors.lastname: Burbage
authors.affiliation: Lymphocyte Interaction Laboratory, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Shweta
authors.initials: S
authors.lastname: Aggarwal
authors.affiliation: Lymphocyte Interaction Laboratory, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Bruno
authors.initials: B
authors.lastname: Frederico
authors.affiliation: Division of Immunology, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
authors.affiliation: Cell Motility Laboratory, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Way
authors.affiliation: Lymphocyte Interaction Laboratory, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bruckbauer
authors.affiliation: Lymphocyte Interaction Laboratory, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. Electronic address: facundo.batista@crick.ac.uk.
authors.forename: Facundo D
authors.initials: FD
authors.lastname: Batista
mesh_terms: D008841:Actin Cytoskeleton / Q000648:ultrastructure; D000199:Actins / Q000032:analysis; D000818:Animals; D000917:Antibody Formation; D018941:Antigens, CD19 / Q000502:physiology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000648:ultrastructure; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D018925:Chemokines / Q000494:pharmacology / Q000502:physiology; D002633:Chemotaxis / Q000187:drug effects; D003598:Cytoskeletal Proteins; D018858:Germinal Center / Q000276:immunology / Q000473:pathology; D006241:Haptens; D006433:Hemocyanins / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D038041:Lymphopoiesis; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation; D010950:Plasma Cells / Q000276:immunology; D011499:Protein Processing, Post-Translational; D011828:Radiation Chimera; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D019707:Receptors, Chemokine / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D059470:Tetraspanins / Q000032:analysis; D014615:Vaccinia / Q000276:immunology / Q000473:pathology
chemical_list: D000199:Actins; D018941:Antigens, CD19; D002352:Carrier Proteins; D018925:Chemokines; D003598:Cytoskeletal Proteins; D006241:Haptens; D006433:Hemocyanins; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D011947:Receptors, Antigen, B-Cell; D019707:Receptors, Chemokine; D059470:Tetraspanins; C098951:4-hydroxy-3-nitrophenylacetyl-keyhole limpet hemocyanin; C491671:Waspip protein, mouse