title: Deregulated cell death and lymphocyte homeostasis cause premature lethality in mice lacking the BH3-only proteins Bim and Bmf.
abstract: BH3 domain-only proteins (BH3-only) proteins are members of the Bcl-2 family that play crucial roles in embryogenesis and the maintenance of tissue homeostasis by triggering apoptotic cell death. The BH3-only protein Bim is critical for developmental apoptosis of lymphocytes, securing establishment of tolerance and for the termination of immune responses. Bim is believed to act in concert with other BH3-only proteins or members of the tumor necrosis factor receptor family in getting rid of unwanted cells. Bmf, a related BH3-only protein, was shown to play a role in B-cell homeostasis and to mediate cell death in response to certain apoptotic triggers, including glucocorticoid, histone deacetylase inhibitors, and overexpression of the c-Myc proto-oncogene. Here we show that Bim and Bmf have overlapping functions during mouse development and coregulate lymphocyte homeostasis and apoptosis in a nonredundant manner. Double deficiency of Bim and Bmf caused more B lymphadenopathy than loss of either BH3-only protein alone, and this was associated with autoimmune glomerulonephritis and a range of malignancies in aged mice. Thus, our results demonstrate that Bim and Bmf act in concert to prevent autoimmunity and malignant disease, strengthening the rational for the development of BH3-only protein mimicking therapeutics for the treatment of such disorders.
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck, Austria;
authors.forename: Verena
authors.initials: V
authors.lastname: Labi
authors.forename: Claudia
authors.initials: C
authors.lastname: Woess
authors.forename: Selma
authors.initials: S
authors.lastname: Tuzlak
authors.forename: Miriam
authors.initials: M
authors.lastname: Erlacher
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000502:physiology; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity; D000072224:Bcl-2-Like Protein 11; D016923:Cell Death; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D006706:Homeostasis; D007107:Immune System; D007136:Immunoglobulins / Q000276:immunology; D008214:Lymphocytes / Q000166:cytology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D060168:Thymocytes / Q000166:cytology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C435486:Bmf protein, mouse; D007136:Immunoglobulins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins