Pyroptosis and Apoptosis Pathways Engage in Bidirectional Crosstalk in Monocytes and Macrophages.
Pyroptosis and Apoptosis Pathways Engage in Bidirectional Crosstalk in Monocytes and Macrophages.
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DOI：
10.1016/j.chembiol.2017.03.009
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发表时间：
2017-04-20
影响因子：
8.6
通讯作者：
Bachovchin DA
中科院分区：
文献类型：
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作者：
Taabazuing CY;Okondo MC;Bachovchin DA
细胞凋亡是由炎症性半胱天冬酶-1、-4和-5介导的程序性细胞死亡的裂解形式。我们最近发现丝氨酸肽酶DPP 8和DPP 9（DPP 8/9）的小分子抑制剂诱导单核细胞和巨噬细胞中的前半胱天冬酶-1依赖性细胞凋亡。值得注意的是，DPP 8/9抑制剂与微生物制剂不同，绝对需要半胱天冬酶-1来诱导细胞死亡。因此，DPP 8/9抑制剂是研究细胞中caspase-1的有用探针。在这里，我们表明，在没有的pyroptosis介导的底物gasdermin D（GSDMD），caspase-1激活caspase-3和-7，并诱导细胞凋亡，表明GSDMD是唯一的caspase-1的底物，诱导pyroptosis。相反，我们发现，在细胞凋亡过程中，半胱天冬酶-3/7通过在与使蛋白失活的炎性半胱天冬酶不同的位点切割GSDMD来特异性阻断细胞凋亡。总的来说，这项工作揭示了单核细胞和巨噬细胞中细胞凋亡和细胞凋亡之间的双向串扰，进一步阐明了先天免疫系统中细胞死亡途径之间的复杂相互作用。
Pyroptosis is a lytic form of programmed cell death mediated by the inflammatory caspases-1, -4, and -5. We recently discovered that small molecule inhibitors of the serine peptidases DPP8 and DPP9 (DPP8/9) induce pro-caspase-1 dependent pyroptosis in monocytes and macrophages. Notably, DPP8/9 inhibitors, unlike microbial agents, absolutely require caspase-1 to induce cell death. Therefore, DPP8/9 inhibitors are useful probes to study caspase-1 in cells. Here we show that, in the absence the pyroptosis-mediating substrate gasdermin D (GSDMD), caspase-1 activates caspases-3 and -7 and induces apoptosis, demonstrating that GSDMD is the only caspase-1 substrate that induces pyroptosis. Conversely, we found that, during apoptosis, caspases-3/7 specifically block pyroptosis by cleaving GSDMD at a distinct site from the inflammatory caspases that inactivates the protein. Overall, this work reveals bidirectional crosstalk between apoptosis and pyroptosis in monocytes and macrophages, further illuminating the complex interplay between cell death pathways in the innate immune system.