title: hsBAFF promotes proliferation and survival in cultured B lymphocytes via calcium signaling activation of mTOR pathway.
abstract: B-cell activating factor of the TNF family (BAFF, also called BLyS, TALL-1, THANK, or zTNF4) has revealed its critical function in B lymphocyte proliferation and survival, as well as the pathogenesis of autoimmune disease. However, the molecular mechanisms of excess BAFF-extended aggressive B lymphocytes have not been completely defined. Here we show that excessive hsBAFF-elevated [Ca(2+)]i activated mammalian target of rapamycin (mTOR) signaling pathway, leading to proliferation and survival in B lymphocytes. This is supported by the findings that intracellular Ca(2+) chelator (BAPTA/AM) or mTOR inhibitor (rapamycin) abolished the events. Sequentially, we observed that preventing [Ca(2+)]i elevation using EGTA or 2-APB dramatically inhibited hsBAFF activation of mTOR signaling, as well as cell growth and survival, suggesting that hsBAFF-induced extracellular Ca(2+) influx and ER Ca(2+) release elevates [Ca(2+)]i contributing to B lymphocyte proliferation and survival via activation of mTOR signaling. Further, we noticed that pretreatment with BAPTA/AM, EGTA or 2-APB blocked hsBAFF-increased phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII), and inhibiting CaMKII with KN93 attenuated hsBAFF-activated mTOR signaling, as well as cell growth and survival, revealing that the effects of hsBAFF-elevated [Ca(2+)]i on mTOR signaling as well as proliferation and survival in B lymphocytes is through stimulating phosphorylation of CaMKII. The results indicate that hsBAFF activates mTOR pathway triggering B lymphocyte proliferation and survival by calcium signaling. Our findings suggest that manipulation of intracellular Ca(2+) level or CaMKII and mTOR activity may be exploited for the prevention of excessive BAFF-induced aggressive B lymphocyte disorders and autoimmune diseases.
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, PR China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Ke
authors.forename: Dingfang
authors.initials: D
authors.lastname: Liang
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Zeng
authors.forename: Qian
authors.initials: Q
authors.lastname: Ren
authors.forename: Hongwei
authors.initials: H
authors.lastname: Ma
authors.forename: Lin
authors.initials: L
authors.lastname: Gui
authors.forename: Sujuan
authors.initials: S
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Guo
authors.forename: Yijiao
authors.initials: Y
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.forename: Shuangquan
authors.initials: S
authors.lastname: Zhang
authors.forename: Long
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D001896:Boron Compounds / Q000737:chemistry; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D053264:B-Cell Activating Factor; D001896:Boron Compounds; D002614:Chelating Agents; D007166:Immunosuppressive Agents; C505719:TNFSF13B protein, human; D004533:Egtazic Acid; C109986:2-aminoethoxydiphenyl borate; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium; D020123:Sirolimus