循环-di-GMP通过直接结合MD2诱导炎症和急性肺损伤
Chenchen Qian1,2, Weiwei Zhu2, Jiong Wang2
1School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China.
Clinical and translational medicine
|August 21, 2024
概括
细胞外循环-di-GMP (CDG) 直接激活髓分化蛋白2 (MD2),触发TLR4通路并导致肺损伤. 阻止MD2可以缓解这种CDG诱导的急性肺损伤 (ALI).
科学领域:
- 传染性疾病 传染性疾病
- 免疫学 免疫学 免疫学
- 肺部病理学 肺部病理学
背景情况:
- 严重的细菌感染可能导致急性肺损伤 (ALI),病原体相关分子模式 (PAMP) 恶化炎症,特别是在COVID-19中.
- 循环-di-GMP (CDG) 是一种细菌PAMP,但细胞外CDG如何触发炎症尚不清楚.
- 此前的研究重点是细胞内CDG的炎症作用.
研究的目的:
- 研究细胞外CDG诱导肺损伤的机制.
- 为了确定细胞外CDG与宿主免疫受体之间的相互作用.
- 探索细菌诱导的ALI的潜在治疗点.
主要方法:
- 在体内和体外模型被用于研究细胞外CDG和骨髓分化蛋白2 (MD2) 的相互作用.
- 使用特定的抑制剂和基因淘汰赛小鼠阻止了MD2.
- 局部定向突变发生,共免疫沉,SPR和Bis-ANS试验确定了CDG上的MD2结合位.
主要成果:
- 细胞外CDG直接与MD2结合,激活托尔类受体4 (TLR4) 信号通路,并导致肺损伤.
- 在小鼠中,MD2抑制或淘汰显著减少了CDG诱导的肺损伤.
- 在MD2上特定的异黄素和氨酸残留物对于CDG结合至关重要.
结论:
- 细胞外CDG通过直接的MD2相互作用和TLR4通路激活诱导肺损伤.
- 这一发现为细菌诱导的ALI机制提供了洞察力.
- 提供了针对细菌共同感染的新疗法的基础,特别是在COVID-19中.
相关概念视频
01:09GPCRs Regulate Adenylyl Cylase Activity
5.4K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
5.4K
01:11IP3/DAG Signaling Pathway
12.0K
Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
12.0K
01:22Activation and Inactivation of G Proteins
6.9K
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
6.9K
01:12GPCR Desensitization
5.9K
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
5.9K
01:16Calmodulin-dependent Signaling
5.1K
Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
5.1K
02:38Mitogens and the Cell Cycle
6.4K
Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.4K