Taabazuing Cornelius Y, Okondo Marian C, Bachovchin Daniel A
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Cell Chem Biol. 2017 Apr 20;24(4):507-514.e4. doi: 10.1016/j.chembiol.2017.03.009. Epub 2017 Apr 6.
Pyroptosis is a lytic form of programmed cell death mediated by the inflammatory caspase-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 of the pyroptosis-mediating substrate gasdermin D (GSDMD), caspase-1 activates caspase-3 and -7 and induces apoptosis, demonstrating that GSDMD is the only caspase-1 substrate that induces pyroptosis. Conversely, we found that, during apoptosis, caspase-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.
细胞焦亡是一种由炎性半胱天冬酶-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DPP8和DPP9（DPP8/9）的小分子抑制剂可在单核细胞和巨噬细胞中诱导前半胱天冬酶-1依赖性细胞焦亡。值得注意的是，与微生物制剂不同，DPP8/9抑制剂绝对需要半胱天冬酶-1来诱导细胞死亡。因此，DPP8/9抑制剂是研究细胞中半胱天冬酶-1的有用探针。在这里，我们表明，在缺乏介导细胞焦亡的底物gasdermin D（GSDMD）的情况下，半胱天冬酶-1激活半胱天冬酶-3和-7并诱导细胞凋亡，这表明GSDMD是唯一能诱导细胞焦亡的半胱天冬酶-1底物。相反，我们发现，在细胞凋亡过程中，半胱天冬酶-3/-7通过在与炎性半胱天冬酶不同的位点切割GSDMD来特异性阻断细胞焦亡，从而使该蛋白失活。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与细胞焦亡之间的双向串扰，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。
