多个未折叠的蛋白质反应通路合作,将细胞质dDNA释放与干扰素激活基因刺激器联系起来
Tiancheng Hu1, Yiping Liu2, Jeremy Fleck3
1Department of Pharmacology and Toxicology, Rutgers University, New Brunswick, NJ, United States.
Frontiers in immunology
|August 5, 2024
概括
细胞内膜网膜应激激活了STING通路,导致IFN-β的产生. 这一过程涉及未展开的蛋白质反应通路和线粒体DNA释放,即使在缺乏直接STING或cGAS连接体的病毒感染期间也是如此.
科学领域:
- 免疫学 免疫学 免疫学
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
背景情况:
- STING (干扰素基因刺激器) 传感器对先天免疫非常重要,它对DNA刺激做出反应.
- 通过未折叠蛋白质反应 (UPR) 的内质网膜 (ER) 应激已与STING激活有关.
- 对于ER应激激活STING并产生连接体的确切机制尚不清楚.
研究的目的:
- 为了调查ER压力是否会产生STING连接体.
- 确定涉及STING激活的特定UPR通路.
- 阐明ER应激在病毒感染期间IFN-β诱导中的作用.
主要方法:
- 用UPR诱导剂刺激细胞 (太普西加金,氧-葡萄糖剥夺).
- 检测IFN-β表达,STING和cGAS依赖性以及细胞质dDNA.
- 抑制UPR通路 (IRE1,PERK) 和相关分子 (XBP1,iNOS,Bim) 的作用.
- 在RNA病毒感染 (VSV) 期间释放dsDNA的分析.
主要成果:
- UPR诱导触发了依赖于STING和cGAS的IFN-β表达.
- ER压力导致细胞质线粒体DNA增加,作为cGAS刺激剂.
- IRE1-XBP1和PERK通路对于细胞质dSDNA生成和释放至关重要.
- IRE1-XBP1下游的活性氧物种 (ROS) 有助于dsDNA释放和IFN-β诱导.
- 作为PERK的标,Bim对于dSDNA释放和IFN-β mRNA诱导至关重要.
- 这些UPR通路还在VSV感染期间调解了STING激活.
结论:
- ER压力通过多个UPR通路激活STING和IFN-β的产生.
- 线粒体dDNA释放是将ER压力与STING激活联系起来的关键机制.
- 这一途径与对缺乏直接STING/cGAS连接体的病毒病原体的先天免疫反应有关.
相关概念视频
Regulation of the Unfolded Protein Response
2.4K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.4K
The Unfolded Protein Response
4.5K
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
4.5K
The JAK-STAT Signaling Pathway
8.7K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
8.7K
NF-κB-dependent Signaling Pathway
7.4K
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The...
NF-κB-dependent Signaling Mechanism
The...
7.4K
Interactions Between Signaling Pathways
6.2K
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.2K
DNA Damage can Stall the Cell Cycle
9.1K
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
9.1K


