Deorphanizing Caspase-3 and Caspase-9 Substrates In and Out of Apoptosis with Deep Substrate Profiling.
Deorphanizing Caspase-3 and Caspase-9 Substrates In and Out of Apoptosis with Deep Substrate Profiling.
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DOI：
10.1021/acschembio.1c00456
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发表时间：
2021-11-19
影响因子：
4
通讯作者：
Julien, Olivier
中科院分区：
文献类型：
--
作者：
Araya, Luam E.;Soni, Ishankumar, V;Hardy, Jeanne A.;Julien, Olivier
半胱氨酸天冬氨酸氨基转移酶是一个酶家族，通过蛋白分解调节炎症和细胞程序性死亡等生物过程。例如，在细胞凋亡的内在途径中，细胞死亡信号涉及细胞色素c从线粒体释放，导致caspase-9激活，最终导致执行者caspase-3和−7的激活。我们理解这些酶的一个关键步骤是确定它们各自的蛋白底物。虽然已经有数百种底物与caspase-3连接，但只有一小部分底物被报道与caspase-9有关。利用枯草杆菌N末端组学的深度分析，我们提出了对天然细胞裂解物中caspase-3和caspase-9底物的无偏见分析。我们确定了906个与caspase-3相关的蛋白底物和124个与caspase-9相关的蛋白底物。这是报道的最全面的caspase底物清单，揭示了用其他方法无法发现的一系列新底物。超过一半的caspase-9底物也被caspase-3切割，但通常是在独特的位置，这表明这两种酶的功能冗余进化。相应地，近一半的caspase-9裂解位点不被caspase-3识别。我们的结果表明，除了它在激活执行者中的重要作用外，Caspase-9的作用可能比先前认识的更广泛和更复杂，包括对关键的凋亡底物的蛋白分解，而不仅仅是Caspase-3和−7，并参与非凋亡途径。我们的研究结果有助于发现这两种半胱氨酸天冬氨酸酶的新生物学功能。
Caspases are a family of enzymes that regulate biological processes such as inflammation and programmed cell death, through proteolysis. For example, in the intrinsic pathway of apoptosis, cell death signaling involves cytochrome c release from the mitochondria, which leads to the activation of caspase-9 and eventually the executioners caspase-3 and −7. One key step in our understanding of these proteases is to identify their respective protein substrates. Although hundreds of substrates have been linked to caspase-3, only a small handful of substrates have been reported for caspase-9. Employing deep profiling by subtiligase N-terminomics, we present here an unbiased analysis of caspase-3 and caspase-9 substrates in native cell lysates. We identified 906 putative protein substrates associated with caspase-3 and 124 protein substrates for caspase-9. This is the most comprehensive list of caspase substrates reported for each of these proteases, revealing a pool of new substrates that could not have been discovered using other approaches. Over half of the caspase-9 substrates were also cleaved by caspase-3, but often at unique sites, suggesting an evolved functional redundancy for these two proteases. Correspondingly, nearly half of the caspase-9 cleavage sites were not recognized by caspase-3. Our results suggest that in addition to its important role in activating the executioners, the role of caspase-9 is likely broader and more complex than previously appreciated, which includes proteolysis of key apoptotic substrates other than just caspase-3 and −7 and involvement in non-apoptotic pathways. Our results are well poised to aid the discovery of new biological functions for these two caspases.
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DOI：
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发表时间：
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期刊：
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影响因子：
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作者：
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