Control of gasdermin D oligomerization and pyroptosis by the Ragulator-Rag-mTORC1 pathway.
Control of gasdermin D oligomerization and pyroptosis by the Ragulator-Rag-mTORC1 pathway.
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DOI：
10.1016/j.cell.2021.06.028
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发表时间：
2021-08-19
期刊：
影响因子：
64.5
通讯作者：
Kagan JC
中科院分区：
文献类型：
--
作者：
Evavold CL;Hafner-Bratkovič I;Devant P;D'Andrea JM;Ngwa EM;Boršić E;Doench JG;LaFleur MW;Sharpe AH;Thiagarajah JR;Kagan JC
焦亡的过程由炎性小体和称为gasdermin D（GSDMD）的下游效应物介导。在被炎性小体相关的半胱天冬酶切割后，GSDMD的N-末端结构域形成促进细胞溶解的膜孔。许多蛋白质促进GSDMD切割，但已知没有一种是GSDMD切割后孔形成所需的。在此，我们报告了一个正向遗传筛选，确定了Ragulator-Rag复合物是GSDMD孔形成和巨噬细胞焦亡所必需的。机制分析显示，Ragulator-Rag不是炎性小体激活后GSDMD切割所需的，而是促进质膜中GSDMD寡聚化。GSDMD寡聚化和孔形成的缺陷可以通过刺激活性氧（ROS）产生的线粒体毒物来挽救，并且ROS调节影响炎性体途径促进GSDMD裂解下游孔形成的能力。这些发现揭示了免疫（炎症体-GSDMD）和代谢（Ragulator-Rag）的关键调节因子之间的意外联系。Ragulator-Rag复合物是Gasdermin D在质膜上的寡聚化以及巨噬细胞中的孔形成和焦亡所必需的。
The process of pyroptosis is mediated by inflammasomes and a downstream effector known as gasdermin D (GSDMD). Upon cleavage by inflammasome-associated caspases, the N-terminal domain of GSDMD forms membrane pores that promote cytolysis. Numerous proteins promote GSDMD cleavage, but none are known to be required for pore formation after GSDMD cleavage. Herein, we report a forward genetic screen that identified the Ragulator-Rag complex as being necessary for GSDMD pore formation and pyroptosis in macrophages. Mechanistic analysis revealed that Ragulator-Rag is not required for GSDMD cleavage upon inflammasome activation, but rather promotes GSDMD oligomerization in the plasma membrane. Defects in GSDMD oligomerization and pore formation can be rescued by mitochondrial poisons that stimulate reactive oxygen species (ROS) production, and ROS modulation impacts the ability of inflammasome pathways to promote pore formation downstream of GSDMD cleavage. These findings reveal an unexpected link between key regulators of immunity (inflammasome-GSDMD) and metabolism (Ragulator-Rag). The Ragulator-Rag complex is required for the oligomerization of gasdermin D at the plasma membrane and for pore formation and pyroptosis in macrophages.
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影响因子：
16
作者：
Andersen, Joshua L.;Kornbluth, Sally
通讯作者：
Kornbluth, Sally
影响因子：
10.9
作者：
Howell, Jessica J.;Manning, Brendan D.
通讯作者：
Manning, Brendan D.
形成孔的蛋白质加油D可以调节白细胞介素-1的巨噬细胞分泌。
影响因子：
32.4
作者：
Evavold CL;Ruan J;Tan Y;Xia S;Wu H;Kagan JC
通讯作者：
Kagan JC
影响因子：
12.4
作者：
de Vasconcelos NM;Van Opdenbosch N;Van Gorp H;Parthoens E;Lamkanfi M
通讯作者：
Lamkanfi M
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE