细胞焦亡“打孔小分队”:GSDMD如何在膜上打孔?

2021-07-26 10:36 来源: BioArt

总的来说,该工作建立了一种能够对细胞焦亡过程中GSDMD介导的膜孔形成的因子进行筛选的实验系统,并且通过正向遗传学筛选鉴定发现了Ragulator-Rag-mTORC1通路对于膜孔形成过程的关键作用,同时探明Ragulator-Rag复合体是通过调控GSDMD的寡聚化而非膜定位从而揭开了其作用的具体分子机制。

值得一提的是,2021年6月25日,来自中科院上海巴斯德研究所的刘星研究员团队与美国哈佛大学医学院Judy Lieberman教授团队在 Science 杂志发表题为The lysosomal Rag-Ragulator complex licenses RIPK1- and Caspase-8-mediated pyroptosis by Yersinia的论文,报道了通过CRISPR/Cas9全基因组敲除筛选鉴定出耶尔森菌感染并触发细胞焦亡的关键因子——Rag-Ragulator复合物,并揭示该复合物激活FADD-RIPK1-Caspase-8(complex Ⅱ)的分子机理(Science丨刘星团队等揭示耶尔森菌诱导细胞焦亡关键机制)。

上述两篇类似的工作共同鉴定到了Ragulator-Rag复合体对细胞焦亡的调控。

原文链接:

https://doi.org/10.1016/j.cell.2021.06.028

参考文献

1 Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666-671, doi:10.1038/nature15541 (2015).

2 Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660-665, doi:10.1038/nature15514 (2015).

3 Chan, A. H. & Schroder, K. Inflammasome signaling and regulation of interleukin-1 family cytokines. The Journal of experimental medicine 217, doi:10.1084/jem.20190314 (2020).

4 Ding, J. et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535, 111-116, doi:10.1038/nature18590 (2016).

5 Aglietti, R. A. et al. GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes. Proceedings of the National Academy of Sciences of the United States of America 113, 7858-7863, doi:10.1073/pnas.1607769113 (2016).

6 Evavold, C. L. et al. The Pore-Forming Protein Gasdermin D Regulates Interleukin-1 Secretion from Living Macrophages. Immunity 48, 35-44.e36, doi:10.1016/j.immuni.2017.11.013 (2018).

7 de Vasconcelos, N. M., Van Opdenbosch, N., Van Gorp, H., Parthoens, E. & Lamkanfi, M. Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture. Cell death and differentiation 26, 146-161, doi:10.1038/s41418-018-0106-7 (2019).

来源:BioArt

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