ORMDL3 Facilitates the Survival of Splenic B Cells via an ATF6α-Endoplasmic Reticulum Stress-Beclin1 Autophagy Regulatory Pathway
ORMDL3 Facilitates the Survival of Splenic B Cells via an ATF6α-Endoplasmic Reticulum Stress-Beclin1 Autophagy Regulatory Pathway
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ORMDL3 通过 ATF6 α-内质网应激-Beclin1 自噬调节途径促进脾 B 细胞的存活
DOI：
10.4049/jimmunol.1602124
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发表时间：
2017-09-01
影响因子：
4.4
通讯作者：
Liu, Qiji
中科院分区：
文献类型：
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作者：
Dang, Jie;Bian, Xianli;Liu, Qiji
类乳清蛋白样蛋白3（ORMDL 3）与一系列免疫炎症性疾病的遗传关联最近已在多个种族群体中被解开，并且功能探索已引起人们对该基因在内质网应激、脂质代谢和炎症反应中的特别相关性的关注。在这项研究中，我们证明了与对照组相比，系统性红斑狼疮患者和狼疮小鼠中ORMDL 3的上调。通过建立ORMDL 3基因敲除小鼠（Ormdl 3（-/-）），我们发现体内沉默Ormdl 3可显著降低脾脏中成熟B淋巴细胞和过渡型2 B细胞以及腹腔灌流液中B1 a细胞的比例、IgG和IgM的分泌以及Baff的表达。此外，敲低Ormdl 3基因可增加脾细胞和脾CD 19（+）B细胞的凋亡，但不影响B细胞的增殖和细胞周期。随后，我们在体外和体内证实了ORMDL 3可能通过ATF 6-Beclin 1自噬途径介导自噬，并通过促进自噬和抑制凋亡促进脾B细胞的存活。总之，我们发现了ORMDL 3在微调B细胞发育和存活中的作用，除了强调ORMDL 3通过ATF 6途径调节自噬的潜在机制之外。
The genetic association of orosomucoid-like 3 (ORMDL3) with an array of immunoinflammatory disorders has been recently unraveled in multiple ethnic groups, and functional exploration has received attention of the particular relevance of this gene in endoplasmic reticulum stress, lipid metabolism, and inflammatory response. In this study, we demonstrated the upregulation of ORMDL3 in both patients with systemic lupus erythematosus and lupus mice compared with controls. By establishing ORMDL3 knockout mice (Ormdl3(-/-)), we showed that silencing Ormdl3 in vivo significantly decreased the proportions of mature B lymphocytes and transitional 2B cells in spleen and B1a cells from abdominal cavity perfusion fluid, the secretion of IgG and IgM, and the expression of Baff. Additionally, knockdown of Ormdl3 augmented the apoptosis of total splenic cells and splenic CD19(+) B cells but did not affect B cell proliferation and cell cycle. Subsequently, we in vitro and in vivo demonstrated that ORMDL3 potentially mediates the autophagy via the ATF 6-Beclin1 autophagy pathway, and it facilitates the survival of splenic B cells via promoting autophagy and suppressing apoptosis. Taken together, we uncovered a role of ORMDL3 in fine-tuning B cell development and survival, besides highlighting a potential mechanism by which ORMDL3 regulates autophagy via ATF6 pathway.