IOCAS-IR  > 实验海洋生物学重点实验室
Thesis Advisor孙黎
Degree Grantor中国科学院大学
Place of Conferral中国科学院海洋研究所
Degree Name理学博士
KeywordGasdermin E Caspase 软体动物 细胞焦亡


在本研究中,我们鉴定了11种软体动物的18GSDM。通过将这些GSDMN terminal (NT)结构域在人类细胞中表达,发现只有皱纹盘鲍(Haliotis discus)的GSDM(命名为HdGSDME)具有诱导细胞焦亡的潜力,而其它10种软体动物的GSDM没有展现出诱导细胞焦亡的能力。通过一系列实验发现并验证了HdGSDME的激活机制。HdGSDME可以被鲍Caspase-3HdCASP3)在两个不同的酶切位点特异性剪切,产生两种不同的N-terminal NT)片段,二者皆具有细胞焦亡诱导活性以及抑菌活性。序列分析表明,HdGSDME拥有保守的氨基酸功能位点,这些关键的氨基酸功能位点对于HdGSDME-NT的成孔活性以及HdGSDME C-terminalCT)的自抑制活性来说是至关重要的。病原菌侵染激活鲍中HdCASP3-HdGSDME通路,并且会引发细胞焦亡以及细胞外陷阱(extracellular trapET)的产生。阻断HdCASP3-HdGSDME通路会促进病原菌在鲍组织内的增殖,并且会导致鲍致死率上升。比较蛋白质组学研究表明,鲍细胞焦亡改变了大量分泌蛋白和非分泌细胞蛋白的表达,暗示细胞焦亡可能诱发复杂的下游反应。


Other Abstract

Gasdermin (GSDM) is a family of proteins that execute pyroptosis in vertebrate. In invertebrate, the studies on GSDM-mediated pyroptosis are scarce. Recent studies identified abundant GSDM structural homologs in Mollusca, but their functions are unknown.

Herein, we screened a total of 18 GSDMs from 11 species of mollusk. By heterologous expression of the N-terminal (NT) domains of these GSDMs in mammalian cells, we found that only the Pacific abalone Haliotis discus GSDM (named HdGSDME) was able to induce pyroptosis, whereas the GSDMs of all the other 10 mollusc were unable to induce pyroptosis. We discovered and verified the activation mechanism of HdGSDME through a series of experiments. HdGSDME was specifically activated by abalone caspase-3 (HdCASP3) cleavage at two distinct sites, generating two active isoforms with pyroptotic and bacteriostatic activities at different rates. Sequence analysis showed that HdGSDME possessed conserved residues that proved to be essential to the N-terminal pore-formation and C-terminal auto-inhibition capacities. Bacterial challenge activated the HdCASP3-HdGSDME pathway and induced pyroptosis and extracellular trap in abalone. Blockage of the HdCASP3-HdGSDME axis promoted bacterial dissemination in abalone tissues and increased host mortality. Comparative proteomic analyses showed that pyroptosis changed the expressions of a large amount of secreted and non-secreted cellular proteins, suggesting that pyroptosis likely induced complex downstream reactions.

In conclusion, our study showed for the first time that GSDME with pyroptotic function existed in mollusc, and revealed the activation mechanism and antibacterial effect of mollusc GSDME represented by HdGSDME. These results added new insights into the mechanisms of programmed cell death in invertebrate.

MOST Discipline Catalogue理学::海洋科学
Document Type学位论文
Recommended Citation
GB/T 7714
秦鹍鹏. 皱纹盘鲍GSDME的激活机制以及免疫功能研究[D]. 中国科学院海洋研究所. 中国科学院大学,2024.
Files in This Item:
File Name/Size DocType Version Access License
皱纹盘鲍GSDME的激活机制以及免疫功能(7278KB)学位论文 暂不开放CC BY-NC-SA
Related Services
Recommend this item
Usage statistics
Export to Endnote
Google Scholar
Similar articles in Google Scholar
[秦鹍鹏]'s Articles
Baidu academic
Similar articles in Baidu academic
[秦鹍鹏]'s Articles
Bing Scholar
Similar articles in Bing Scholar
[秦鹍鹏]'s Articles
Terms of Use
No data!
Social Bookmark/Share
All comments (0)
No comment.

Items in the repository are protected by copyright, with all rights reserved, unless otherwise indicated.