Developmental change in translation initiation alters the localization of a common microbial protein necessary for Toxoplasma chronic infection.
Developmental change in translation initiation alters the localization of a common microbial protein necessary for Toxoplasma chronic infection.
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DOI：
10.1111/mmi.13538
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发表时间：
2016-12
影响因子：
3.6
通讯作者：
Knoll LJ
中科院分区：
文献类型：
--
作者：
Milligan-Myhre K;Wilson SK;Knoll LJ
刚地弓形虫囊肿期对药物治疗有耐药性。为了确定新疗法的潜在靶点，我们筛选了弓形虫的插入突变体，以降低小鼠大脑中形成囊肿的能力。在其中一种名为38C3的突变体中，诱变质粒插入一种蛋白质的mRNA中，这种蛋白质在微生物中高度保守，但在人类中不存在。38C3突变导致慢性感染期间脑囊肿产生减少，但不影响急性毒力，因此被破坏的基因和蛋白被称为弓形虫脑定植蛋白1 （TgBCP1）。TgBCP1在框架内有三个潜在的启动密码子，分别产生51、33或25 kDa蛋白。在快速复制的速殖子中，翻译从第三个蛋氨酸开始，产生在许多细菌和原生动物中保守的25 kDa形式。脑囊肿只表达51 kDa形式的TgBCP1，该基因由寄生虫分泌并定位于囊肿壁。在38C3突变体中，只有长型TgBCP1的表达才能恢复囊肿的形成。TgBCP1对囊肿形成至关重要，是弓形虫蛋白翻译起始位点偏好发育调控的第一个例子。一种弓形虫突变体在微生物中高度保守的蛋白质中被破坏，但在人类中不存在，在慢性感染期间在小鼠大脑中产生较少的囊肿。在细胞培养中，该蛋白的翻译开始于第三个蛋氨酸，产生25 kDa的形式，而在脑囊肿中，翻译开始于第一个蛋氨酸，产生51 kDa的形式，由寄生虫分泌并定位于囊肿壁。
The Toxoplasma gondii cyst stage is resistant to drug therapy. To identify potential targets for new therapeutics, we screened insertional mutants of T. gondii for a reduced ability to form cysts in the brains of mice. In one of these mutants, named 38C3, the mutagenesis plasmid inserted into the mRNA of a protein that is highly conserved in microbes but is not present in humans. The mutation in 38C3 causes reduced brain cyst production during chronic infection, but does not affect acute virulence, so the disrupted gene and protein are called T. gondii Brain Colonization Protein 1 (TgBCP1). TgBCP1 has three potential in frame start codons that produce either 51, 33 or 25 kDa proteins. In rapidly replicating tachyzoites, translation initiates at the third methionine, producing the 25 kDa form that is conserved in many bacteria and protozoans. Brain cysts exclusively express the 51 kDa form of TgBCP1, which is secreted from the parasites and localizes to the cyst wall. Only expression of the long form of TgBCP1 restored cyst formation in the 38C3 mutant. TgBCP1 is essential for cyst formation and is the first example of a developmental regulation in translation initiation site preference for a T. gondii protein. A Toxoplasma mutant that is disrupted in a protein highly conserved in microbes but is not present in humans, produces fewer cysts in mouse brains during chronic infection. In cell culture, translation of this protein initiates at the third methionine to produce a 25 kDa form, whereas in brain cysts translation begins at the first methionine to produce a 51 kDa form that is secreted from the parasites and localizes to the cyst wall.
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影响因子：
4.4
作者：
Hehl AB;Basso WU;Lippuner C;Ramakrishnan C;Okoniewski M;Walker RA;Grigg ME;Smith NC;Deplazes P
通讯作者：
Deplazes P
影响因子：
3.1
作者：
Tobin, Crystal M.;Knoll, Laura J.
通讯作者：
Knoll, Laura J.
影响因子：
3.7
作者：
Fritz HM;Buchholz KR;Chen X;Durbin-Johnson B;Rocke DM;Conrad PA;Boothroyd JC
通讯作者：
Boothroyd JC
DOI：
10.1073/pnas.0701893104
发表时间：
2007-06-12
影响因子：
11.1
作者：
Frankel, Matthew B.;Mordue, Dana G.;Knoll, Laura J.
通讯作者：
Knoll, Laura J.
真核纤毛的蛋白质组学分析。
影响因子：
7.8
作者：
Pazour, Gregory J;Agrin, Nathan;Leszyk, John;Witman, George B
通讯作者：
Witman, George B