The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8.
The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8.
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代谢物 alpha-KG 通过死亡受体 6 激活的 caspase-8 诱导 GSDMC 依赖性细胞焦亡
DOI：
10.1038/s41422-021-00506-9
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发表时间：
2021-09
期刊：
影响因子：
44.1
通讯作者：
Wu Q
中科院分区：
文献类型：
--
作者：
Zhang JY;Zhou B;Sun RY;Ai YL;Cheng K;Li FN;Wang BR;Liu FJ;Jiang ZH;Wang WJ;Zhou D;Chen HZ;Wu Q
焦亡是由gasdermin家族成员介导的一种调节性细胞死亡形式，其中GSDMC的功能尚未明确描述。在此，我们证明代谢产物α-酮戊二酸（α-KG）通过半胱天冬酶-8介导的GSDMC裂解诱导细胞焦亡。DM-αKG（α-KG的细胞渗透性衍生物）治疗可升高ROS水平，导致质膜定位的死亡受体DR 6氧化。DR 6的氧化触发其内吞作用，然后通过蛋白质-蛋白质相互作用将胱天蛋白酶原-8和GSDMC两者募集到DR 6受体体。本文中的DR 6受体体提供了通过活性胱天蛋白酶-8切割GSDMC的平台，从而导致焦亡。此外，这种α-KG诱导的焦亡可以抑制小鼠模型中的肿瘤生长和转移。有趣的是，α-KG诱导细胞凋亡的效率依赖于酸性环境，其中α-KG被MDH 1还原并转化为L-2 HG，进一步提高ROS水平。用糖酵解的终产物乳酸处理，建立了一个改善的酸性环境，以促进更多的L-2 HG的产生，这使得原本抗焦亡的癌细胞更容易受到α-KG诱导的焦亡的影响。本研究不仅阐明了与代谢物相关的焦萎途径，而且还确定了一个未报道的主轴，该主轴从ROS引发的DR 6内吞作用延伸到胱天蛋白酶8介导的GSDMC切割，用于肿瘤治疗的潜在临床应用。
Pyroptosis is a form of regulated cell death mediated by gasdermin family members, among which the function of GSDMC has not been clearly described. Herein, we demonstrate that the metabolite α-ketoglutarate (α-KG) induces pyroptosis through caspase-8-mediated cleavage of GSDMC. Treatment with DM-αKG, a cell-permeable derivative of α-KG, elevates ROS levels, which leads to oxidation of the plasma membrane-localized death receptor DR6. Oxidation of DR6 triggers its endocytosis, and then recruits both pro-caspase-8 and GSDMC to a DR6 receptosome through protein-protein interactions. The DR6 receptosome herein provides a platform for the cleavage of GSDMC by active caspase-8, thereby leading to pyroptosis. Moreover, this α-KG-induced pyroptosis could inhibit tumor growth and metastasis in mouse models. Interestingly, the efficiency of α-KG in inducing pyroptosis relies on an acidic environment in which α-KG is reduced by MDH1 and converted to L-2HG that further boosts ROS levels. Treatment with lactic acid, the end product of glycolysis, builds an improved acidic environment to facilitate more production of L-2HG, which makes the originally pyroptosis-resistant cancer cells more susceptible to α-KG-induced pyroptosis. This study not only illustrates a pyroptotic pathway linked with metabolites but also identifies an unreported principal axis extending from ROS-initiated DR6 endocytosis to caspase-8-mediated cleavage of GSDMC for potential clinical application in tumor therapy.
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影响因子：
4.1
作者：
Afzal, I;Cunningham, P;Naftalin, RJ
通讯作者：
Naftalin, RJ
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.0604044103
发表时间：
2006-07-05
影响因子：
11.1
作者：
Austin, Cary D.;Lawrence, David A.;Ashkenazi, Avi
通讯作者：
Ashkenazi, Avi
影响因子：
5.9
作者：
Calabrese C;Iommarini L;Kurelac I;Calvaruso MA;Capristo M;Lollini PL;Nanni P;Bergamini C;Nicoletti G;Giovanni CD;Ghelli A;Giorgio V;Caratozzolo MF;Marzano F;Manzari C;Betts CM;Carelli V;Ceccarelli C;Attimonelli M;Romeo G;Fato R;Rugolo M;Tullo A;Gasparre G;Porcelli AM
通讯作者：
Porcelli AM
RIP3 的裂解通过去除激酶结构域使其不依赖 caspase 的细胞凋亡途径失活
影响因子：
4.8
作者：
Feng, Shanshan;Yang, Yonghui;Wu, Mian
通讯作者：
Wu, Mian