The cyclic AMP phosphodiesterase RegA critically regulates encystation in social and pathogenic amoebas.
The cyclic AMP phosphodiesterase RegA critically regulates encystation in social and pathogenic amoebas.
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DOI：
10.1016/j.cellsig.2013.10.008
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发表时间：
2014-02
影响因子：
4.8
通讯作者：
Schaap P
中科院分区：
文献类型：
--
作者：
Du Q;Schilde C;Birgersson E;Chen ZH;McElroy S;Schaap P
变形虫通过分化成包囊而在环境压力下生存。作为包囊，致病性阿米巴抵抗抗生素，这特别抵消了对破坏视力的阿米巴角膜炎的治疗。阿米巴病原体有限的遗传易处理性使其成囊机制尚未探索。社会性变形虫盘状网柄变形虫（Dictyosteelium discoideum）在多细胞子实体中形成孢子以在饥饿中生存，而其他网柄变形虫（如Polysphondyosteelium pallidum）可以额外地以单细胞包囊。孢子形成由cAMP作用于PKA诱导，cAMP磷酸二酯酶RegA严格调节cAMP水平。我们在这里表明，RegA在社会和致病性阿米巴中是高度保守的，并且在苍白球中RegA基因的缺失会导致早熟包囊形成并防止包囊萌发。我们异源表达和表征阿米巴RegA，并进行化合物筛选，以确定RegA抑制剂。两种有效的抑制剂增加cAMP水平，并触发阿米巴包囊。我们的研究结果表明，RegA严格调节阿米巴成囊，cAMP信号通路的组成部分可能是有效的治疗干预与成囊的目标。阿米巴在环境胁迫下分化为休眠包囊包囊，包囊包囊形成使致病性阿米巴对抗生素和杀虫剂产生抗性。社会性阿米巴苍白多软骨藻适合于通过遗传学方法来解决包囊形成机制。cAMP磷酸二酯酶RegA和调节RegA活性的传感器组氨酸激酶是高度保守的。RegA调节苍白多软骨藻和病原体卡氏阿米巴的包囊形成。
Amoebas survive environmental stress by differentiating into encapsulated cysts. As cysts, pathogenic amoebas resist antibiotics, which particularly counteracts treatment of vision-destroying Acanthamoeba keratitis. Limited genetic tractability of amoeba pathogens has left their encystation mechanisms unexplored. The social amoeba Dictyostelium discoideum forms spores in multicellular fruiting bodies to survive starvation, while other dictyostelids, such as Polysphondylium pallidum can additionally encyst as single cells. Sporulation is induced by cAMP acting on PKA, with the cAMP phosphodiesterase RegA critically regulating cAMP levels. We show here that RegA is deeply conserved in social and pathogenic amoebas and that deletion of the RegA gene in P. pallidum causes precocious encystation and prevents cyst germination. We heterologously expressed and characterized Acanthamoeba RegA and performed a compound screen to identify RegA inhibitors. Two effective inhibitors increased cAMP levels and triggered Acanthamoeba encystation. Our results show that RegA critically regulates Amoebozoan encystation and that components of the cAMP signalling pathway could be effective targets for therapeutic intervention with encystation. Amoebas differentiate into dormant encapsulated cysts when exposed to environmental stress Encystation renders pathogenic amoebas resistant to antibiotics and biocides The social amoeba Polysphondylium pallidum is amenable to genetic approaches to resolve encystation mechanisms The cAMP phosphodiesterase RegA and the sensor histidine kinases that regulate RegA activity are deeply conserved RegA regulates encystation in P.pallidum and in the pathogen Acanthamoeba castellani
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影响因子：
5.1
作者：
Abd, H;Weintraub, A;Sandström, G
通讯作者：
Sandström, G
影响因子：
4.8
作者：
Coppi, A;Merali, S;Eichinger, D
通讯作者：
Eichinger, D
影响因子：
11.4
作者：
HOPPER, NA;HARWOOD, AJ;WILLIAMS, JG
通讯作者：
WILLIAMS, JG
影响因子：
3.5
作者：
Kawabe, Y;Enomoto, T;Tanaka, Y
通讯作者：
Tanaka, Y
影响因子：
6.4
作者：
Panjwani, Noorjahan
通讯作者：
Panjwani, Noorjahan