The chaperone Hsp90 and PPIases of the cyclophilin and FKBP families facilitate membrane translocation of Photorhabdus luminescens ADP‐ribosyltransferases
The chaperone Hsp90 and PPIases of the cyclophilin and FKBP families facilitate membrane translocation of Photorhabdus luminescens ADP‐ribosyltransferases
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亲环蛋白和 FKBP 家族的分子伴侣 Hsp90 和 PPIase 促进发光杆菌 ADP 核糖基转移酶的膜易位
DOI：
10.1111/cmi.12228
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发表时间：
2014
影响因子：
3.4
通讯作者：
Aktories
中科院分区：
文献类型：
--
作者：
Papatheodorou;Schwan;Aktories
发光菌的TccC3和TccC5是ADP核糖基转移酶，它们分别修饰肌动蛋白和Rho GTP酶，从而诱导肌动蛋白的聚合和聚集。细菌蛋白质是细菌毒素复合体的组成部分，由结合和转位成分TcdA1、建议的连接子成分TcdB2和酶成分TccC3/5组成。虽然毒素对靶蛋白的作用已经明确，但对毒素摄取和转运到靶细胞胞浆中的了解还不是很清楚。在这里，我们通过使用药物抑制剂显示，热休克蛋白90(Hsp90)和包括亲环素和FK506结合蛋白(FKBPs)在内的多肽脯氨酸顺式/转移酶(PPIase)促进ADP核糖化毒素进入宿主细胞胞浆。抑制HSP90和/或PPIase导致靶细胞中毒减少，这是由细胞圆化和细胞单层跨上皮电阻降低所确定的。Hsp90和PPIase的抑制剂不能抑制毒素的ADP-核糖基转移酶活性和毒素诱导的孔道形成。这些毒素与Hsp90、FKBP51、Cyp40和CypA相互作用，提示这些宿主细胞因子在ADP-核糖基转移酶的易位和/或重折叠中起作用。
TccC3 and TccC5 fromPhotorhabdus luminescensare ADP‐ribosyltransferases, which modify actin and Rho GTPases, respectively, thereby inducing polymerization and clustering of actin. The bacterial proteins are components of thePhotorhabdustoxin complexes, consisting of the binding and translocation component TcdA1, a proposed linker component TcdB2 and the enzymatic component TccC3/5. While the action of the toxins on target proteins is clearly defined, uptake and translocation of the toxins into the cytosol of target cells are not well understood. Here we show by using pharmacological inhibitors that heat shock protein 90 (Hsp90) and peptidyl prolylcis/transisomerases (PPIases) including cyclophilins and FK506‐binding proteins (FKBPs) facilitate the uptake of the ADP‐ribosylating toxins into the host cell cytosol. Inhibition of Hsp90 and/or PPIases resulted in decreased intoxication of target cells byPhotorhabdustoxin complexes determined by cell rounding and reduction of transepithelial electrical resistance of cell monolayers. ADP‐ribosyltransferase activity of toxins and toxin‐induced pore formation were notimpaired by the inhibitors of Hsp90 and PPIases. ThePhotorhabdustoxins interacted with Hsp90, FKBP51, Cyp40 and CypA, suggesting a role of these host cell factors in translocation and/or refolding of the ADP‐ribosyltransferases.
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DOI：
10.1016/j.bbamcr.2011.11.006
发表时间：
2012-03
影响因子：
5.1
作者：
Sanchez, Edwin R.
通讯作者：
Sanchez, Edwin R.
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
影响因子：
4.8
作者：
Giesemann, T;Jank, T;Aktories, K
通讯作者：
Aktories, K
影响因子：
3.1
作者：
Kaiser, Eva;Kroll, Claudia;Barth, Holger
通讯作者：
Barth, Holger
影响因子：
4
作者：
Stechschulte, Lance A.;Sanchez, Edwin R.
通讯作者：
Sanchez, Edwin R.