Lymphotoxin α induces apoptosis, necroptosis and inflammatory signals with the same potency as tumour necrosis factor
Lymphotoxin α induces apoptosis, necroptosis and inflammatory signals with the same potency as tumour necrosis factor
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DOI：
10.1111/febs.12419
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发表时间：
2013-11-01
期刊：
影响因子：
5.4
通讯作者：
Nachbur, Ueli
中科院分区：
文献类型：
--
作者：
Etemadi, Nima;Holien, Jessica K.;Nachbur, Ueli
两种TNF超家族配体TNF和LT α都可以通过TNFR 1和TNFR 2结合并发出信号，但每种突变体的小鼠具有不同的表型。这种差异的部分原因是因为LT α而不是TNF可以激活疱疹病毒进入介体，并且还与LT β异源三聚化以激活LT β R，这与LT α和LT β R缺陷小鼠的相似表型一致。然而，也有报道称LT α（3）同源三聚体通过TNFR 1与TNF不同地发出信号，并且在一些炎性疾病的起始和恶化中具有独特的作用。我们对TNF/TNFR 1界面与LT α（3）/TNFR 1结构的模型比较揭示了一些差异，这些差异可能影响两种配体的信号传导。为了确定TNF和LT α 3诱导TNFR 1依赖性细胞凋亡或坏死性凋亡的能力是否存在任何功能差异，以及cIAP和Sharpin传递TNFR 1信号的需求是否不同，我们比较了细胞对TNF和LT α 3的反应能力。与我们的假设相反，我们无法发现TNFR 1对TNF和LT α的反应信号的差异（3）。我们的研究结果表明，LT α保守的原因最有可能是由于差异调节，通过疱疹病毒进入介体或LT α与LT β形成异源三聚体的能力信号的能力。
Both of the TNF superfamily ligands, TNF and LT alpha, can bind and signal through TNFR1 and TNFR2, yet mice mutant for each have different phenotypes. Part of this difference is because LT alpha but not TNF can activate Herpes Virus Entry Mediator and also heterotrimerise with LT beta to activate LT beta R, which is consistent with the similar phenotypes of the LT alpha and LT beta R deficient mice. However, it has also been reported that the LT alpha(3) homotrimer signals differently than TNF through TNFR1, and has unique roles in initiation and exacerbation of some inflammatory diseases. Our modeling of the TNF/TNFR1 interface compared to the LT alpha(3)/TNFR1 structure revealed some differences that could affect signalling by the two ligands. To determine whether there were any functional differences in the ability of TNF and LT alpha 3 to induce TNFR1-dependent apoptosis or necroptosis, and if there were different requirements for cIAPs and Sharpin to transmit the TNFR1 signal, we compared the ability of cells to respond to TNF and LT alpha(3). Contrary to our hypothesis, we were unable to discover differences in signalling by TNFR1 in response to TNF and LT alpha(3). Our results imply that the reasons for the conservation of LT alpha are most likely due either to differential regulation, the ability to signal through Herpes Virus Entry Mediator or the ability of LT alpha to form heterotrimers with LT beta.