BAFF inhibits autophagy promoting cell proliferation and survival by activating Ca2+-CaMKII-dependent Akt/mTOR signaling pathway in normal and neoplastic B-lymphoid cells

Abstract

B cell activating factor from the TNF family (BAFF) is implicated in not only the physiology of normal B cells, but also the pathophysiology of aggressive B cells related to malignant and autoimmune diseases. Autophagy plays a crucial role in balancing the beneficial and detrimental effects of immunity and inflammation. However, little is known about whether and how excessive BAFF mediates autophagy contributing to B-cell proliferation and survival. Here, we show that excessive human soluble BAFF (hsBAFF) inhibited autophagy with a concomitant reduction of LC3-II in normal and B-lymphoid (Raji) cells. Knockdown of LC3 not only potentiated hsBAFF inhibition of autophagy, but also attenuated hsBAFF activation of Akt/mTOR pathway, thereby diminishing hsBAFF-induced B-cell proliferation/viability. Further, we found that hsBAFF inhibition of autophagy was Akt/mTOR-dependent. This is supported by the findings that hsBAFF increased mTORC1-mediated phosphorylation of ULK1 (Ser757); Akt inhibitor X, mTORC1 inhibitor rapamycin, mTORC1/2 inhibitor PP242, expression of dominant negative Akt, or knockdown of mTOR attenuated hsBAFF-induced phosphorylation of ULK1, decrease of LC3-II level, and increase of cell proliferation/viability. Chelating intracellular free Ca2+ ([Ca2+]i) with BAPTA/AM or preventing [Ca2+]i elevation using EGTA or 2-APB profoundly blocked hsBAFF-induced activation of Akt/mTOR, phosphorylation of ULK1 and decrease of LC3-II, as well as increase of cell proliferation/viability. Similar effects were observed in the cells where CaMKII was inhibited by KN93 or knocked down by CaMKII shRNA. Collectively, these results indicate that hsBAFF inhibits autophagy promoting cell proliferation and survival through activating Ca2+-CaMKII-dependent Akt/mTOR signaling pathway in normal and neoplastic B-lymphoid cells. Our findings suggest that manipulation of intracellular Ca2+ level or CaMKII, Akt, or mTOR activity to promote autophagy may be exploited for prevention of excessive BAFF-induced aggressive B lymphocyte disorders and autoimmune diseases.

MicroRNA-92a-3p enhances functional recovery and suppresses apoptosis after spinal cord injury via targeting phosphatase and tensin homolog

“…Knocking out or inhibiting PTEN has been reported to be able to induce the regenerative abilities of multiple neuronal populations such as corticospinal neurons, dorsal root ganglion, retinal ganglion cells and sensory neurons [37][38][39]. In addition, PTEN also functions as an inhibitor to AKT/mTOR pathway [40], which plays an important role in cell proliferation and survival [41,42]. In AKT/mTOR pathway, phosphoinositide 3-kinases (PI3Ks) convert phosphatidylinositol (4,5)-bisphosphate (PIP2) into phosphatidylinositol (3,4,5)-trisphosphate (PIP3), subsequently activates Akt, mTOR and ribosomal protein (S6), ultimately realizing its neuroprotective effects [43].…”

Role of Autophagy in Lung Inflammation

“…Due to the critical role of autophagy in these cells, it may provide a therapeutic target. For example, specific phenotypes of disease, such as B cell activating factor from the TNF family (BAFF) induced inflammatory diseases could be targeted through regulation of intracellular Ca 2+ level or CaMKII, AKT, or mTOR ultimately regulating autophagy and attenuating disease (155). Increased levels of BAFF have been observed in child asthma patients compared to healthy children (156).…”

Protection effect of gastrodin on learning and memory ability in vascular dementia by promoting autophagy flux via Ca2+/CaMKII signal pathway

“…The depletion of energy induced by cerebral blood flow in VD patients induces the accumulation of free calcium in the cells [53]. The increase of cytoplasmic Ca 2+ could enhancethe binding of Ca 2+ -CaM complex to the regulatory domain of CaMKII, increase the activity of CaMKII, and then activate autophagy [26,41]. Hippocampus and cerebral cortex are the structural basis of spatial learning, CaMKⅡ is the molecular basis of spatial learning and memory [54].…”

“…Ca 2+ is considered to be a crucial regulator of autophagy and calcium signal is closely related to the occurrence and development of autophagy [41]. Therefore, we further explore the mechanism of whether GAS can attenuate CoCl 2 -induced inhibition autophagy flux by regulating [Ca 2+ ] i -dependent CaMKII phosphorylation in HT22 cells.…”