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  • 人类 GSDME 把各种半胱氨酸蛋白酶 (rCASPs)以 p20/10 花样切割(GSDME 的 N 头序列被标注)

  • GSDME 介导化疗药物诱导小鼠毒性作用的尝试

  • Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin

    Nature volume547, pages99–103 (06 July 2017)doi:10.1038/nature22393

    yupeng Wang1,2*;Wenqing Gao1,2*;Xuyan Shi1,2;Jingjin Ding2,3;Wang liu2;Huabin He2;Kun Wang2 & Feng Shao2,4

    2017年

    重点作者:王玉鹏;高文青

    打电话作者:邵峰

    生物学院

           Pyroptosis is a form of cell death that is critical for immunity. It can be induced by the canonical caspase-1 inflammasomes or by activation of caspase-4, -5 and -11 by cytosolic lipopolysaccharide1,2,3. The caspases cleave gasdermin D (GSDMD) in its middle linker to release autoinhibition on its gasdermin-N domain, which executes pyroptosis via its pore-forming activity4,5,6,7,8,9. GSDMD belongs to a gasdermin family that shares the pore-forming domain4,6,10. The functions and mechanisms of activation of other gasdermins are unknown. Here we show that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5)11, can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis. GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis. After chemotherapy, cleavage of GSDME by caspase-3 induced pyroptosis in certain GSDME-expressing cancer cells. GSDME was silenced in most cancer cells but expressed in many normal tissues. Human primary cells exhibited GSDME-dependent pyroptosis upon activation of caspase-3 by chemotherapy drugs. Gsdme−/− (also known as Dfna5−/−) mice were protected from chemotherapy-induced tissue damage and weight loss. These findings suggest that caspase-3 activation can trigger necrosis by cleaving GSDME and offer new insights into cancer chemotherapy.

           细胞死亡一般包括细胞凋亡(Apoptosis)、坏死(Necrosis)和焦亡(Pyroptosis)。前不久来细胞焦亡逐渐把认为是细胞死亡领域一个奇异重大的哲学过程。咱实验室在2015年发现了细胞焦亡的实行过程中特有重要的一个蛋白分子:Gasdermin-D/GSDMD。非激活状态下,GSDMD的蛋白质N头和C头处在自抑制状态,顶上游信号(Inflammatory Caspases: Caspase-1/4/11)把激活后,GSDMD的蛋白N头和C头连接区域被炎症性天冬氨酸蛋白酶(Caspase-1/4/11)切割,人家N头释放出来上细胞膜寡聚打孔,因而引起细胞焦亡,同时伴随着细胞因子(IL-1β/IL-18)的自由1。GSDMD属于Gasdermin蛋白家族的一个成员,有趣的是,其一家族的其他蛋白质也具有自抑制的特色,并且这些蛋白的N头也得以上膜打孔,进而引起细胞焦亡。2
           我之研讨专题就是集中在这个家族的另一番成员GSDME,顶我们在Hela细胞里稳定发挥GSDME时,用TNFα和CHX共刺激,细胞会发生非常明确的焦亡;对人家蛋白序列分析,咱发现在GSDME蛋白的N头和C头连接处,有一番奇异经典的Caspase-3辨认切割序列(DMPD)。穿越细胞和生化实验,咱证明了GSDME可以把Caspase-3霎时切割,顶把第一氨基酸(270位天冬氨酸)突变后则无从把切割。检测多株细胞系后我们发现,GSDME在大部分残疾细胞里不表态,而在原代细胞里高表达。咱挑选了两株高表达GSDME的癌症细胞以及三株原代细胞,证明了在化疗药的打算下,那些细胞Caspase-3把激活,进而通过切割GSDME引起细胞焦亡。当前临床上采取的大部分化疗药都是通过引起DNA损伤,进而激活Caspase-3来诱导癌症细胞死亡的,但是这些药品会引起非常明确的副作用,咱猜想GSDME也许在化疗药引起的副作用里边起了重点作用。之所以王凤超先生帮助我们做了Gsdme 敲除的小鼠;送野生型小鼠注射化疗药物“顺铂”,可以引起小鼠肺部炎症的产生,同样也得以引起肠道的损伤;而Gsdme 敲除的小鼠则会明白的控制这种损伤;同时我们也做了更多种类之针灸药物(5-FU,bleomycin),那些化疗药物引起的肺部或者肠道损伤也得以在Gsdme敲除的小鼠上得到很好的缓解。3
           归纳来说,咱发现GSDME是Caspase-3的哲理底物,并且决定了Caspase-3激活之后,细胞走向哪种细胞死亡 (凋亡还是焦亡),如果细胞里边表达了GSDME,这就是说细胞就会走向焦亡,引起炎症反应;此外我们证明GSDME在化疗药引起机体副作用上班了重大的打算。3
           1.Jianjin Shi, Yue Zhao, et al., Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature, 2015, 526.660-665.
           2.Jingjin Ding, Kun Wang, et al., Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 2016, 535. 111-116.
           3.Yupeng Wang, Wenqing Gao, et al., Chemtherapy drugs induce pyroptosis through caspase-3 cleavage a gasdermin. Nature, 2017, 547.99-103.

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