MLKL激活了cGAS-STING通路,通过在诱导亡后释放线粒体DNA来激活该通路
Zhangcheng Ding1, Rui Wang2, Yuhua Li3
1Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing 100084, PRC; National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, PRC; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 100084, PRC.
Molecular cell
|July 4, 2025
概括
混合基因酶类蛋白MLKL触发了亡,释放了线粒体DNA (mtDNA) 来激活cGAS-STING通路并促进炎症. 抑制这种途径可以在炎症性肠病模型中减少炎症.
科学领域:
- 细胞生物学 细胞生物学
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
背景情况:
- 亡是一种被编程的细胞死亡途径,涉及混合血统酶样蛋白 (MLKL).
- 激活MLKL会导致血破裂,并释放与损伤相关的分子模式 (DAMPs).
- MLKL在线粒体DAMP释放和随后的免疫激活中的作用尚未完全理解.
研究的目的:
- 研究MLKL在线粒体DNA (mtDNA) 释放中的作用.
- 为了确定释放的mtDNA是否激活cGAS-STING通路.
- 评估向cGAS-STING通路在死细胞灭绝中介炎症中的治疗潜力.
主要方法:
- 使用了对死细胞灭和炎性肠病 (IBD) 的小鼠模型.
- 使用细胞生物学技术研究MLKL局部化.
- 评估mtDNA释放及其对cGAS-STING通路的影响.
- 与cGAS-STING通路干扰,以评估治疗效果.
主要成果:
- 化MLKL (-MLKL) 转移到线粒体,诱导微管体依赖mtDNA的释放.
- 释放的mtDNA激活了干扰素基因 (cGAS-STING) 路径的循环GMP-AMP合成酶刺激器,从而调节干扰素β (Ifnb).
- 在IBD小鼠模型中,cGAS-STING通路的抑制减少了炎症并改善了肠道的恢复.
结论:
- MLKL通过细胞自主 (mtDNA释放) 和细胞非自主 (DAMP释放) 机制诱导炎症.
- 通过MLKL介导的mtDNA释放激活了cGAS-STING通路,从而导致死细胞灭绝引起的炎症.
- 向cGAS-STING通路代表了与亡相关的炎症性疾病 (如IBD) 的潜在治疗策略.
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