Location bias contributes to functionally selective responses of biased CXCR3 agonists.
Location bias contributes to functionally selective responses of biased CXCR3 agonists.
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DOI：
10.1038/s41467-022-33569-2
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发表时间：
2022-10-04
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
一些G蛋白偶联受体（GPCR）配体作为“偏向激动剂”，优先激活特定的信号转导。虽然GPCR主要存在于质膜，但GPCR可以运输到许多亚细胞区室并从许多亚细胞区室发出信号。在这里，我们确定，差异亚细胞信号有助于产生的GPCR CXC趋化因子受体3（CXCR 3）的三个内源性配体的偏置信号。当CXCR 3以配体特异性方式从质膜运输到内体时，其信号传导谱发生变化。内体信号传导对于G蛋白、β-抑制蛋白和细胞外信号调节激酶（ERK）的偏性激活至关重要。在CD 8 + T细胞中，趋化因子促进独特的转录反应，预测调节炎症途径。在接触性超敏反应的小鼠模型中，β-抑制蛋白偏向的CXCR 3介导的炎症依赖于受体内化。我们的工作表明，不同的亚细胞信号传导对在CXCR 3观察到的整体偏倚反应至关重要，这对靶向趋化因子受体和其他GPCR的药物具有重要意义。亚细胞信号传导对于在趋化因子受体CXCR 3处产生调节炎症途径的细胞应答至关重要。Eiger等人确定激动剂偏向的CXCR 3信号在内体处不同于质膜处，提出位置偏向是信号转导中的重要现象。
Some G protein-coupled receptor (GPCR) ligands act as “biased agonists” that preferentially activate specific signaling transducers over others. Although GPCRs are primarily found at the plasma membrane, GPCRs can traffic to and signal from many subcellular compartments. Here, we determine that differential subcellular signaling contributes to the biased signaling generated by three endogenous ligands of the GPCR CXC chemokine receptor 3 (CXCR3). The signaling profile of CXCR3 changes as it traffics from the plasma membrane to endosomes in a ligand-specific manner. Endosomal signaling is critical for biased activation of G proteins, β-arrestins, and extracellular-signal-regulated kinase (ERK). In CD8 + T cells, the chemokines promote unique transcriptional responses predicted to regulate inflammatory pathways. In a mouse model of contact hypersensitivity, β-arrestin-biased CXCR3-mediated inflammation is dependent on receptor internalization. Our work demonstrates that differential subcellular signaling is critical to the overall biased response observed at CXCR3, which has important implications for drugs targeting chemokine receptors and other GPCRs. Subcellular signaling is critical to generating cellular responses that modulate inflammatory pathways at the chemokine receptor CXCR3. Eiger et al. determine that agonist-biased CXCR3 signaling at endosomes differs from that at the plasma membrane, proposing location bias as an important phenomenon in signal transduction.
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影响因子：
4.8
作者：
Eiger DS;Boldizsar N;Honeycutt CC;Gardner J;Rajagopal S
通讯作者：
Rajagopal S
DOI：
10.1074/jbc.m116.754887
发表时间：
2016-12-30
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Alvarez-Curto E;Inoue A;Jenkins L;Raihan SZ;Prihandoko R;Tobin AB;Milligan G
通讯作者：
Milligan G
突变动力蛋白的诱导特异性阻断内吞涂层囊泡的形成。
影响因子：
7.8
作者：
Damke, H;Baba, T;Warnock, D E;Schmid, S L
通讯作者：
Schmid, S L
影响因子：
5.3
作者：
Colvin, Richard A.;Campanella, Gabriele S. V.;Luster, Andrew D.
通讯作者：
Luster, Andrew D.
影响因子：
64.8
作者：
Eichel K;Jullié D;Barsi-Rhyne B;Latorraca NR;Masureel M;Sibarita JB;Dror RO;von Zastrow M
通讯作者：
von Zastrow M