Compartmentalized Cyclic AMP Production by the Bordetella pertussis and Bacillus anthracis Adenylate Cyclase Toxins Differentially Affects the Immune Synapse in T Lymphocytes.
Compartmentalized Cyclic AMP Production by the Bordetella pertussis and Bacillus anthracis Adenylate Cyclase Toxins Differentially Affects the Immune Synapse in T Lymphocytes.
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DOI：
10.3389/fimmu.2018.00919
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发表时间：
2018
影响因子：
7.3
通讯作者：
Baldari CT
中科院分区：
文献类型：
--
作者：
Arumugham VB;Ulivieri C;Onnis A;Finetti F;Tonello F;Ladant D;Baldari CT
免疫突触 (IS) 的一个核心特征是膜受体和信号传导介质的紧密区隔，其功能在于协调 T 细胞激活。参与这一过程的第二信使，例如 Ca2+ 和二酰基甘油，也在 IS 处经历区室化。目前的证据表明，环磷酸腺苷 (cAMP) 的情况更为复杂，它既充当 T 细胞抗原受体 (TCR) 信号传导的正调节剂，又充当负调节剂，因此必须受到严格的时空控制，以允许 IS 处的信号传导。在这里，我们使用了两种细菌腺苷酸环化酶毒素，即百日咳博德特氏菌 CyaA 和炭疽杆菌水肿毒素 (ET)，它们由于其不同的细胞入侵途径而在不同的亚细胞定位处产生 cAMP，以解决 T 细胞将 cAMP 限制在产生位点的能力，并解决区室化 cAMP 产生对 IS 组装和功能的影响。我们发现，CyaA 在靠近突触膜处产生 cAMP，不仅通过调节 LFA-1 及其伴侣 talin 和 L-plastin 的分布（如之前部分报道），还通过促进 A 激酶接头蛋白 ezrin 和蛋白激酶 A 的持续突触积累，同时抑制 β-arrestin 介导的磷酸二酯酶 4B 的募集，从而影响 IS 稳定性。这些效应取决于毒素的催化活性，并且可以通过用不可水解的 cAMP 类似物处理来重现。值得注意的是，尽管 ET 能够通过其 cAMP 升高活性抑制 TCR 信号传导和 T 细胞活化，但 ET 不会引起任何这些效应，因为 ET 在核周定位产生 cAMP。这些结果表明，IS 仅对 cAMP 的局部升高做出反应，并提供了证据，表明 T 细胞中有效的区室化机制可将 cAMP 包含在靠近产生位点的位置，即使在超生理水平产生时也是如此。
A central feature of the immune synapse (IS) is the tight compartmentalization of membrane receptors and signaling mediators that is functional for its ability to coordinate T cell activation. Second messengers centrally implicated in this process, such as Ca2+ and diacyl glycerol, also undergo compartmentalization at the IS. Current evidence suggests a more complex scenario for cyclic AMP (cAMP), which acts both as positive and as negative regulator of T-cell antigen receptor (TCR) signaling and which, as such, must be subjected to a tight spatiotemporal control to allow for signaling at the IS. Here, we have used two bacterial adenylate cyclase toxins that produce cAMP at different subcellular localizations as the result of their distinct routes of cell invasion, namely Bordetella pertussis CyaA and Bacillus anthracis edema toxin (ET), to address the ability of the T cell to confine cAMP to the site of production and to address the impact of compartmentalized cAMP production on IS assembly and function. We show that CyaA, which produces cAMP close to the synaptic membrane, affects IS stability by modulating not only the distribution of LFA-1 and its partners talin and L-plastin, as previously partly reported but also by promoting the sustained synaptic accumulation of the A-kinase adaptor protein ezrin and protein kinase A while suppressing the β-arrestin-mediated recruitment of phosphodiesterase 4B. These effects are dependent on the catalytic activity of the toxin and can be reproduced by treatment with a non-hydrolyzable cAMP analog. Remarkably, none of these effects are elicited by ET, which produces cAMP at a perinuclear localization, despite its ability to suppress TCR signaling and T cell activation through its cAMP-elevating activity. These results show that the IS responds solely to local elevations of cAMP and provide evidence that potent compartmentalization mechanisms are operational in T cells to contain cAMP close to the site of production, even when produced at supraphysiological levels.
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影响因子：
32.4
作者：
Das, V;Nal, B;Alcover, A
通讯作者：
Alcover, A
DOI：
10.1152/ajpcell.2001.281.5.c1468
发表时间：
2001-11-01
影响因子：
5.5
作者：
Hirshman, CA;Zhu, DF;Emala, CW
通讯作者：
Emala, CW
DOI：
10.1007/978-3-642-17969-3_15
发表时间：
2011-01-01
期刊：
PHOSPHODIESTERASES AS DRUG TARGETS
影响因子：
--
作者：
Bjorgo, Elisa;Moltu, Kristine;Tasken, Kjetil
通讯作者：
Tasken, Kjetil
影响因子：
15.9
作者：
Liu, Shihui;Moayeri, Mahtab;Leppla, Stephen H.
通讯作者：
Leppla, Stephen H.
DOI：
10.1083/jcb.200503032
发表时间：
2005-07-18
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lin J;Miller MJ;Shaw AS
通讯作者：
Shaw AS