Mouse Cd59b but not Cd59a is upregulated to protect cells from complement attack in response to inflammatory stimulation
Mouse Cd59b but not Cd59a is upregulated to protect cells from complement attack in response to inflammatory stimulation
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DOI：
10.1038/gene.2015.29
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发表时间：
2015-07
影响因子：
5
通讯作者：
Jianfeng Chen;Yiqun Du;Peipei Ding;Xin Zhang;Longfu Zhang;Na Wang;Weiguo Hu
中科院分区：
文献类型：
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作者：
Jianfeng Chen;Yiqun Du;Peipei Ding;Xin Zhang;Longfu Zhang;Na Wang;Weiguo Hu
CD59是唯一一种普遍表达的膜补体调节蛋白，通过限制膜攻击复合体的组装来保护宿主细胞免受补体损伤。人类基因编码一个单一的CD59，而老鼠基因编码一个重复的CD59，包括mCD59a和mCD59b，具有不同的组织分布。最近，我们发现Sp1调控CD59的结构性转录，而活化B细胞的核因子-kappa轻链增强子(NF-κB)和环磷酸腺苷反应元件结合蛋白(CREB)调控诱导的CD59转录。然而，mCD59调控的机制仍不清楚。在这里，我们证明Sp1控制广泛分布的mCD59a的表达，而血清反应因子和典型的NF-κB调节选择性表达的mCD59b。体外的肿瘤坏死因子-α和体内的脂多糖通过激活SRF和NF-κB而显著增强mCD59b的表达，而不是mCD59a的表达，从而保护细胞免受补体攻击。此外，cAMP类似物处理也显著增加mCD59b而不是mCD59a的表达，这种方式不依赖于CREB、SRF和NF-κB。因此，mCD59b而不是mCD59a可能是对外部炎症刺激的反应者，并可能在补体介导的疾病模型中发挥重要作用。
Universally expressed CD59 is the sole membrane complement regulatory protein that protects host cells from complement damage by restricting membrane attack complex assembly. The human gene encodes a single CD59, whereas the mouse gene encodes a duplicated CD59, comprising mCd59a and mCd59b, with distinct tissue distribution. Recently, we revealed that Sp1 regulates constitutive CD59 transcription and that canonical nuclear factor kappa light chain enhancer of activated B cells (NF-κB) and cyclic AMP-responsive element-binding protein (CREB) regulate inducible CD59 transcription. However, the mechanisms that underlie mCd59 regulation remain unclear. Here we demonstrate that Sp1 controls broadly distributed mCd59a expression, whereas serum response factor (SRF) and canonical NF-κB regulate selectively expressed mCd59b. Tumor necrosis factor-α in vitro and lipopolysaccharide in vivo remarkably enhance the expression of mCd59b but not mCd59a by activating SRF and NF-κB, thus protecting cells from complement attack. In addition, cAMP analog treatment also dramatically increases mCd59b but not mCd59a expression in a manner independent of CREB, SRF and NF-κB. Therefore, mCd59b but not mCd59a may be the responder to external inflammatory stimuli and may have an important role in complement-mediated mouse models of disease.