title: A requirement for the p85 PI3K adapter protein BCAP in the protection of macrophages from apoptosis induced by endoplasmic reticulum stress.
abstract: Macrophages are innate immune cells that play key roles in regulation of the immune response and in tissue injury and repair. In response to specific innate immune stimuli, macrophages may exhibit signs of endoplasmic reticulum (ER) stress and progress to apoptosis. Factors that regulate macrophage survival under these conditions are poorly understood. In this study, we identified B cell adapter protein (BCAP), a p85 PI3K-binding adapter protein, in promoting survival in response to the combined challenge of LPS and ER stress. BCAP was unique among nine PI3K adapter proteins in being induced >10-fold in response to LPS. LPS-stimulated macrophages incubated with thapsigargin, a sarcoplasmic/endoplasmic reticulum calcium ATPase inhibitor that induces ER stress, underwent caspase-3 activation and apoptosis. Macrophages from BCAP(-/-) mice exhibited increased apoptosis in response to these stimuli. BCAP-deficient macrophages demonstrated decreased activation of Akt, but not ERK, and, unlike BCAP-deficient B cells, expressed normal amounts of the NF-κB subunits, c-Rel and RelA. Retroviral transduction of BCAP-deficient macrophages with wild-type BCAP, but not a Y4F BCAP mutant defective in binding the SH2 domain of p85 PI3K, reversed the proapoptotic phenotype observed in BCAP-deficient macrophages. We conclude that BCAP is a nonredundant PI3K adapter protein in macrophages that is required for maximal cell survival in response to ER stress. We suggest that as macrophages engage their pathogenic targets, innate immune receptors trigger increased expression of BCAP, which endows them with the capacity to withstand further challenges from ongoing cellular insults, such as ER stress.
authors.affiliation: Program in Biotechnology, Columbia University, New York, NY 10032, USA.
authors.forename: SungWon
authors.initials: S
authors.lastname: Song
authors.forename: Claude
authors.initials: C
authors.lastname: Chew
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Dale
authors.forename: Daniel
authors.initials: D
authors.lastname: Traum
authors.forename: James
authors.initials: J
authors.lastname: Peacock
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Raphael
authors.initials: R
authors.lastname: Clynes
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kurosaki
authors.forename: Steven
authors.initials: S
authors.lastname: Greenberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000276:immunology; D004721:Endoplasmic Reticulum / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007113:Immunity, Innate; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism / Q000502:physiology; D008264:Macrophages / Q000166:cytology* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D013312:Stress, Physiological / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008024:Ligands; D008070:Lipopolysaccharides; C487978:Pik3ap1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases