由ACOD1介导的溶酶体膜通透性有助于由Mycobacterium结核病诱导的巨细胞死亡
Ziwei Yang1, Li Zhang2, Samantha Ottavi3
1Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065.
概括
结核菌菌的感染触发了干扰素-β,导致ACOD1的诱导. 虽然伊塔科纳特保护,但ACOD1非酶性降解HSP70,导致巨细胞的溶解体细胞死亡.
科学领域:
- 免疫学 免疫学 免疫学
- 细胞生物学 细胞生物学
- 微生物学 微生物学
背景情况:
- 结核菌菌 (Mtb) 感染了巨细胞,导致细胞死亡.
- 干扰素-β (IFN-β) 加剧了Mtb诱导的巨细胞死亡.
- Mtb诱导的巨细胞死亡的机制尚未完全理解.
研究的目的:
- 研究Mtb感染的巨细胞中对IFN-β的下游反应.
- 确定参与MTb诱导的巨细胞死亡的关键蛋白质.
- 阐明cis-aconitate脱碳酶 (ACOD1) 在这个过程中的作用.
主要方法:
- 在Mtb感染的巨细胞中研究了ACOD1的诱导和局部化.
- 评估了 ACOD1.1 的酶和非酶功能.
- 研究了ACOD1,HSP70和溶酶体之间的相互作用.
- 评估了ACOD1和囊蛋白酶抑制剂对巨细胞死亡的影响.
主要成果:
- IFN-β在线粒体和细胞质中诱导大规模的ACOD1表达.
- ACOD1在细胞质中结合HSP70,促进其降解.
- ACOD1的非酶活性导致溶酶体膜通透 (LMP) 和巨细胞死亡.
- 伊塔科纳酸,ACOD1的产品,显示出保护作用,与ACOD1的主导死亡促进作用形成对比.
结论:
- 在Mtb感染的巨细胞中,ACOD1扮演着双重的角色:通过非酶 HSP70 降解产生保护性伊塔科纳酸并促进细胞死亡.
- lysosome介导的细胞死亡是Mtb诱导的巨细胞死亡的一个关键机制.
- 针对 ACOD1 的非酶功能或 HSP70 降解,需要进一步研究宿主导结核病疗法.
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