Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo.
Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo.
复制标题
DOI：
10.1038/s41598-021-84817-2
复制
发表时间：
2021-03-08
影响因子：
4.6
通讯作者：
Barth H
中科院分区：
文献类型：
--
作者：
Ernst K;Mittler AK;Winkelmann V;Kling C;Eberhardt N;Anastasia A;Sonnabend M;Lochbaum R;Wirsching J;Sakari M;Pulliainen AT;Skerry C;Carbonetti NH;Frick M;Barth H
百日咳是由百日咳杆菌引起的，百日咳杆菌释放百日咳毒素（PT），其包含酶A亚基PTS 1和结合/转运B亚基。在受体介导的内吞作用后，PT到达内质网，未折叠的PTS 1从内质网被转运到胞质溶胶。PTS 1 ADP-核糖基化G蛋白α-亚基，导致cAMP信号传导增加。在这里，证明了靶细胞分子伴侣Hsp 90，Hsp 70，亲环蛋白和FK 506结合蛋白对细胞溶质PTS 1摄取的作用。PTS 1在体外和细胞中特异性地和直接地与分子伴侣相互作用。特异性药理学伴侣抑制通过减少细胞内PTS 1量而不影响细胞结合或酶活性，保护CHO-K1、人原代气道基底细胞和完全分化的气道上皮细胞免受PT中毒。PT被人气道上皮分泌细胞而不是纤毛细胞内化，并导致顶端表面液体增加。亲环素抑制剂减少百日咳幼鼠模型中的白细胞增多，表明它们在开发新的百日咳治疗策略方面具有很大的潜力。
Whooping cough is caused by Bordetella pertussis that releases pertussis toxin (PT) which comprises enzyme A-subunit PTS1 and binding/transport B-subunit. After receptor-mediated endocytosis, PT reaches the endoplasmic reticulum from where unfolded PTS1 is transported to the cytosol. PTS1 ADP-ribosylates G-protein α-subunits resulting in increased cAMP signaling. Here, a role of target cell chaperones Hsp90, Hsp70, cyclophilins and FK506-binding proteins for cytosolic PTS1-uptake is demonstrated. PTS1 specifically and directly interacts with chaperones in vitro and in cells. Specific pharmacological chaperone inhibition protects CHO-K1, human primary airway basal cells and a fully differentiated airway epithelium from PT-intoxication by reducing intracellular PTS1-amounts without affecting cell binding or enzyme activity. PT is internalized by human airway epithelium secretory but not ciliated cells and leads to increase of apical surface liquid. Cyclophilin-inhibitors reduced leukocytosis in infant mouse model of pertussis, indicating their promising potential for developing novel therapeutic strategies against whooping cough.
登录
查看更多内容
影响因子：
3.4
作者：
Fahrer, Joerg;Kuban, Jasmin;Barth, Holger
通讯作者：
Barth, Holger
影响因子：
4.2
作者：
Ernst, Katharina;Eberhardt, Nina;Barth, Holger
通讯作者：
Barth, Holger
DOI：
10.1111/j.1600-0463.2010.02664.x
发表时间：
2010-12
期刊：
APMIS : acta pathologica, microbiologica, et immunologica Scandinavica
影响因子：
--
作者：
Dalby T;Sørensen C;Petersen JW;Krogfelt KA
通讯作者：
Krogfelt KA
影响因子：
3.4
作者：
Dmochewitz L;Lillich M;Kaiser E;Jennings LD;Lang AE;Buchner J;Fischer G;Aktories K;Collier RJ;Barth H
通讯作者：
Barth H
DOI：
10.1098/rspb.2015.2309
发表时间：
2016-01-13
影响因子：
4.7
作者：
de Celles, Matthieu Domenech;Magpantay, Felicia M. G.;Rohani, Pejman
通讯作者：
Rohani, Pejman