The arginine-rich N-terminal domain of ROP18 is necessary for vacuole targeting and virulence of Toxoplasma gondii.
The arginine-rich N-terminal domain of ROP18 is necessary for vacuole targeting and virulence of Toxoplasma gondii.
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DOI：
10.1111/cmi.12022
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发表时间：
2012-12
影响因子：
3.4
通讯作者：
Sibley LD
中科院分区：
文献类型：
--
作者：
Fentress SJ;Steinfeldt T;Howard JC;Sibley LD
刚地弓形虫在入侵宿主细胞时，利用一种叫做弓形虫体的特殊分泌细胞器将毒力决定因子传递到宿主细胞。其中一种决定因素被称为腺状体蛋白18 (ROP18)，它是一种多态丝氨酸/苏氨酸激酶，可磷酸化宿主靶点以调节急性毒力。在分泌到宿主细胞后，ROP18运输到寄生物液泡膜（PVM），在那里它被束缚在宿主-病原体界面的细胞质表面。然而，PVM关联的功能后果尚不清楚。在这篇报道中，我们发现ROP18突变体在激酶结构域上游的一个富含精氨酸的结构域发生了改变，在rhopys分泌后不能与PVM结合。在感染期间，宿主细胞上调免疫相关的gtpase，该gtpase定位并破坏寄生虫周围的PVM。ROP18通过磷酸化关键GTPase结构域的IRGs并阻止PVM上的负载，解除了宿主先天免疫途径。ROP18液泡靶向突变体不能磷酸化Irga6，也不能将IRGs从PVM转移，尽管保留了内在的激酶活性。结果，这些突变体在急性弓形虫病小鼠模型中是无毒的。因此，通过其n端富含精氨酸结构域介导的ROP18与PVM的关联，对其作为毒力决定因素的功能至关重要。
Toxoplasma gondii uses specialized secretory organelles called rhoptries to deliver virulence determinants into the host cell during parasite invasion. One such determinant called rhoptry protein 18 (ROP18) is a polymorphic serine/threonine kinase that phosphorylates host targets to modulate acute virulence. Following secretion into the host cell, ROP18 traffics to the parasitophorous vacuole membrane (PVM) where it is tethered to the cytosolic face of this host-pathogen interface. However, the functional consequences of PVM association are not known. In this report, we show that ROP18 mutants altered in an arginine-rich domain upstream of the kinase domain fail to associate to the PVM following secretion from rhoptries. During infection, host cells up-regulate immunity-related GTPases that localize to and destroy the PVM surrounding the parasites. ROP18 disarms this host innate immune pathway by phosphorylating IRGs in a critical GTPase domain and preventing loading on the PVM. Vacuole-targeting mutants of ROP18 failed to phosphorylate Irga6 and were unable to divert IRGs from the PVM, despite retaining intrinsic kinase activity. As a consequence, these mutants were avirulent in a mouse model of acute toxoplasmosis. Thus, the association of ROP18 with the PVM, mediated by its N-terminal arginine-rich domain, is critical to its function as a virulence determinant.
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影响因子：
6.7
作者：
Martens S;Parvanova I;Zerrahn J;Griffiths G;Schell G;Reichmann G;Howard JC
通讯作者：
Howard JC
影响因子：
3.4
作者：
Khaminets A;Hunn JP;Könen-Waisman S;Zhao YO;Preukschat D;Coers J;Boyle JP;Ong YC;Boothroyd JC;Reichmann G;Howard JC
通讯作者：
Howard JC
影响因子：
4
作者：
Fentress, Sarah J.;Sibley, L. David
通讯作者：
Sibley, L. David
影响因子：
6.7
作者：
Liu L;Westler WM;den Boon JA;Wang X;Diaz A;Steinberg HA;Ahlquist P
通讯作者：
Ahlquist P
影响因子：
16.8
作者：
Drin, Guillaume;Casella, Jean-Francois;Antonny, Bruno
通讯作者：
Antonny, Bruno