Third target of rapamycin complex negatively regulates development of quiescence in Trypanosoma brucei
Third target of rapamycin complex negatively regulates development of quiescence in Trypanosoma brucei
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DOI：
10.1073/pnas.1210465109
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发表时间：
2012-09-04
影响因子：
11.1
通讯作者：
Navarro, Miguel
中科院分区：
文献类型：
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作者：
Barquilla, Antonio;Saldivia, Manuel;Navarro, Miguel
非洲锥虫是通过采采蝇媒介传播给哺乳动物宿主的原生动物寄生虫。生命周期包括高度增殖型和静止型，后者适合宿主传播。控制这两种形式之间发育转换的信号通路仍然未知。布氏锥虫含有两种雷帕霉素靶蛋白（TOR）激酶TbTOR1和TbTOR2，以及两种TOR复合物TbTORC1和TbTORC2。令人惊讶的是，在T.布鲁氏菌基因组我们报告说，TbTOR4协会与犰狳结构域的蛋白质（TbArmtor），一个主要的穹窿蛋白，和LST 8形成一个独特的TOR复合物，TbTORC4。TbTOR4的耗尽导致寄生虫不可逆地分化为静止形式。AMP和cAMP的水解类似物抑制TbTOR 4的表达，并诱导短的静止形式。我们的研究结果揭示了TOR信号转导中意想不到的复杂性，并表明TbTORC4负调控增殖形式向静止形式的分化。
African trypanosomes are protozoan parasites transmitted by a tsetse fly vector to a mammalian host. The life cycle includes highly proliferative forms and quiescent forms, the latter being adapted to host transmission. The signaling pathways controlling the developmental switch between the two forms remain unknown. Trypanosoma brucei contains two target of rapamycin (TOR) kinases, TbTOR1 and TbTOR2, and two TOR complexes, TbTORC1 and TbTORC2. Surprisingly, two additional TOR kinases are encoded in the T. brucei genome. We report that TbTOR4 associates with an Armadillo domain-containing protein (TbArmtor), a major vault protein, and LST8 to form a unique TOR complex, TbTORC4. Depletion of TbTOR4 caused irreversible differentiation of the parasite into the quiescent form. AMP and hydrolysable analogs of cAMP inhibited TbTOR4 expression and induced the stumpy quiescent form. Our results reveal unexpected complexity in TOR signaling and show that TbTORC4 negatively regulates differentiation of the proliferative form into the quiescent form.