title: Deletion of cIAP1 and cIAP2 in murine B lymphocytes constitutively activates cell survival pathways and inactivates the germinal center response.
abstract: B cells require signals delivered through B-cell activating factor of the TNF family receptor (BAFF-R) and CD40 to survive and produce antibody responses in vivo. In vitro data indicate that these signals are controlled by the homologous RING finger proteins cIAP1 and cIAP2, in collaboration with TRAF2 and TRAF3. There is also mounting evidence that all 4 of these signaling molecules can act as tumor suppressors in human B-lineage malignancies. However, it has not been possible to identify the roles of cIAP1 and cIAP2 in controlling B-cell physiology because of the absence of an appropriate in vivo model. Here we describe a unique genetically modified mouse in which the linked cIap1 and cIap2 genes can be independently inactivated. Deletion of cIAP1 plus cIAP2 (but not either protein alone) rendered primary B cells independent of BAFF-R for their survival and led to their uncontrolled accumulation in vivo. B cells deficient in cIAP1 and cIAP2 were also incapable of forming germinal centers, a key step in antibody-mediated immunity. These data define a fundamental role for cIAP1/cIAP2 in regulating B-cell survival and responsiveness, show this requires direct binding to TRAF2, and suggest how mutations of TRAF2, TRAF3, and cIAP1/cIAP2 contribute to B-lineage malignancies, such as multiple myeloma.
authors.affiliation: Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gardam
authors.forename: Vivian M
authors.initials: VM
authors.lastname: Turner
authors.forename: Holly
authors.initials: H
authors.lastname: Anderton
authors.forename: Sandhya
authors.initials: S
authors.lastname: Limaye
authors.forename: Antony
authors.initials: A
authors.lastname: Basten
authors.forename: Frank
authors.initials: F
authors.lastname: Koentgen
authors.forename: David L
authors.initials: DL
authors.lastname: Vaux
authors.forename: John
authors.initials: J
authors.lastname: Silke
authors.forename: Robert
authors.initials: R
authors.lastname: Brink
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000378:metabolism; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology* / Q000502:physiology*; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D019013:CD40 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D017353:Gene Deletion; D018858:Germinal Center / Q000166:cytology* / Q000502:physiology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D019013:CD40 Antigens; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; C486662:Tnfrsf13c protein, mouse; C505720:Tnfsf13b protein, mouse; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494834:Birc2 protein, mouse; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases