Secretory Protein Profiling Reveals TNF-α Inactivation by Selective and Promiscuous Sec61 Modulators
Secretory Protein Profiling Reveals TNF-α Inactivation by Selective and Promiscuous Sec61 Modulators
复制标题
DOI：
10.1016/j.chembiol.2011.06.015
复制
发表时间：
2011-09-23
影响因子：
--
通讯作者：
Taunton, Jack
中科院分区：
文献类型：
--
作者：
Maifeld, Sarah V.;MacKinnon, Andrew L.;Taunton, Jack
共转蛋白是一种环七肽，结合Sec61易位子抑制分泌和I型跨膜蛋白亚群的共翻译易位。少数已知的协转蛋白敏感底物都是通过可切割的信号序列靶向转座子的，这在以前被证明是协转蛋白敏感性的关键决定因素。通过分析两种共转蛋白变体对一组分泌蛋白和跨膜蛋白的影响，我们证明了共转蛋白侧链的差异深刻地影响了底物的选择性。其中最敏感的底物是促炎细胞因子肿瘤坏死因子（tnf - α）。像所有II型跨膜蛋白一样，tnf - α通过其跨膜结构域靶向转座子，这表明可切割的信号序列对协转蛋白的敏感性并不严格要求。因此，我们的研究结果揭示了Sec61调节剂抑制易位底物表达的出乎意料的广度。
Cotransins are cyclic heptadepsipeptides that bind the Sec61 translocon to inhibit cotranslational translocation of a subset of secreted and type I transmembrane proteins. The few known cotransin-sensitive substrates are all targeted to the translocon by a cleavable signal sequence, previously shown to be a critical determinant of cotransin sensitivity. By profiling two cotransin variants against a panel of secreted and transmembrane proteins, we demonstrate that cotransin side-chain differences profoundly affect substrate selectivity. Among the most sensitive substrates we identified is the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha). Like all type II transmembrane proteins, TNF-alpha is targeted to the translocon by its membrane-spanning domain, indicating that a cleavable signal sequence is not strictly required for cotransin sensitivity. Our results thus reveal an unanticipated breadth of translocon substrates whose expression is inhibited by Sec61 modulators.