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.

Grape seed proanthocyanidins protect against streptozotocin‑induced diabetic nephropathy by attenuating endoplasmic reticulum stress‑induced apoptosis

“…A variety of factors, including ischemia, hypoxia, glucose starvation, heat shock and Ca 2+ overload, can disturb ER function and result in ERS ( 9 ). Gentle ERS can protect cells from damage, but prolonged or severe stress leads to apoptosis ( 22 – 24 ). ERS is evident in various renal diseases, including primary glomerulonephritides, acute kidney injury, chronic kidney disease, renal fibrosis, glomerulopathies associated with genetic mutations and DN.…”

Quantum and All-Atom Molecular Dynamics Simulations of Protonation and Divalent Ion Binding to Phosphatidylinositol 4,5-Bisphosphate (PIP2)

“…These methods are consistent with quantum mechanical (QM) calculations performed on other biomolecules parameterized in classical force fields 9,21,22 . Charges were calculated using CHarges from ELectrostatic Potentials using a Grid based method (CHELPG) 10,11,23 . The vibrational eigenvalues and eigenvectors were computed at HF/6-31G model chemistry and after applying suitable scaling factors 12-15,24 compared with ATR-FTIR experimental data on supported bilayers containing PIP 2 8,16 .…”

Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K

“…2). 21,94,97 BCAP mechanistically connects TLRs to PI3K through a cryptic TIR domain at the N terminus of BCAP, which is utilized for recruitment to the TLR signaling apparatus (Fig. 1).…”