title: Essential role for caspase-8 in Toll-like receptors and NFkappaB signaling.
abstract: In addition to its pro-apoptotic function in the death receptor pathway, roles for caspase-8 in mediating T-cell proliferation, maintaining lymphocyte homeostasis, and suppressing immunodeficiency have become evident. Humans with a germline point mutation of CASPASE-8 have multiple defects in T cells, B cells, and NK cells, most notably attenuated activation and immunodeficiency. By generating mice with B-cell-specific inactivation of caspase-8 (bcasp8(-/-)), we show that caspase-8 is dispensable for B-cell development, but its loss in B cells results in attenuated antibody production upon in vivo viral infection. We also report an important role for caspase-8 in maintaining B-cell survival following stimulation of the Toll-like receptor (TLR)2, -3, and -4. In response to TLR4 stimulation, caspase-8 is recruited to a complex containing IKKalphabeta, and its loss resulted in delayed NFkappaB nuclear translocation and impaired NFkappaB transcriptional activity. Our study supports dual roles for caspase-8 in apoptotic and nonapoptotic functions and demonstrates its requirement for TLR signaling and in the regulation of NFkappaB function.
authors.affiliation: Ontario Cancer Institute, University of Toronto, Toronto, Ontario M5G 2C1, Canada.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Lemmers
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salmena
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bidère
authors.forename: Helen
authors.initials: H
authors.lastname: Su
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Matysiak-Zablocki
authors.forename: Kiichi
authors.initials: K
authors.lastname: Murakami
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: Andrea
authors.initials: A
authors.lastname: Jurisicova
authors.forename: Michael
authors.initials: M
authors.lastname: Lenardo
authors.forename: Razqallah
authors.initials: R
authors.lastname: Hakem
authors.forename: Anne
authors.initials: A
authors.lastname: Hakem
mesh_terms: D000818:Animals; D053181:Caspase 8 / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology*; D010766:Phosphorylation; D018353:Rhabdoviridae Infections / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D014721:Vesicular stomatitis Indiana virus; D019014:fas Receptor / Q000502:physiology
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019014:fas Receptor; D053181:Caspase 8