Toxoplasma gondii stabilises tetrameric complexes of tyrosine‐phosphorylated signal transducer and activator of transcription‐1 and leads to its sustained and promiscuous DNA binding
Toxoplasma gondii stabilises tetrameric complexes of tyrosine‐phosphorylated signal transducer and activator of transcription‐1 and leads to its sustained and promiscuous DNA binding
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弓形虫稳定酪氨酸磷酸化信号转导子和转录激活子 1 的四聚体复合物，并导致其持续且混杂的 DNA 结合
DOI：
10.1111/cmi.12887
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发表时间：
2018
影响因子：
3.4
通讯作者：
Carsten G. K.
中科院分区：
文献类型：
--
作者：
Roswitha;Thomas;Lüder;Carsten G. K.
弓形虫是一种专性细胞内寄生虫，感染全世界高达30%的人类。它可能导致严重疾病，特别是对于免疫反应不成熟或有缺陷的个体。刚地弓形虫的控制依赖于IFN-γ诱导的信号转导子和转录激活子-1（STAT 1）通路，而刚地弓形虫的STAT 1依赖性转录抑制因子（TgIST）主要抑制STAT 1介导的基因转录。在这里，我们分析了STAT 1的要求，结合TgIST和STAT 1信号转导的下游影响的特点。TgIST与STAT 1二聚体结合，但更有效地与STAT 1四聚体组装，这对有效的IFN-γ应答至关重要。这种结合在STAT 1的N-末端而不是C-末端缺失突变体中被废除。此外，TgIST不与不能形成STAT 1四聚体的STAT 1F 77 A取代突变体结合，导致寄生虫感染的STAT 1F 77 A表达细胞对IFN-γ完全无反应性。值得注意的是，TgIST的结合显著增加了异常STAT 1四聚体对DNA共有序列结合基序的亲和力，甚至能够与非共有序列结合。与DNA结合增加一致，来自寄生虫感染细胞的STAT 1在Tyr 701和Ser 727处保持磷酸化，并以DNA结合状态保留在细胞核内。持续和混杂的结合活性，特别是STAT 1四聚体与缺乏共有STAT 1结合基序的非特异性DNA位点的结合活性，是一种尚未认识到的机制，导致了弓形虫感染细胞中IFN-γ介导的信号传导缺陷。
Toxoplasma gondiiis an obligate intracellular parasite that infects up to 30% of humans worldwide. It can lead to severe diseases particularly in individuals with immature or defective immune responses. Control ofT. gondiirelies on the IFN‐γ‐induced signal transducer and activator of transcription‐1 (STAT1) pathway.T. gondii, however, largely inactivates STAT1‐mediated gene transcription byT. gondiiinhibitor of STAT1‐dependent transcription (TgIST), a parasite effector protein binding to STAT1. Here, we have analysed requirements of STAT1 to bind TgIST and characterised downstream effects on STAT1 signalling. TgIST bound to STAT1 dimers but more efficiently assembled with STAT1 tetramers, which are essential for effective IFN‐γ responsiveness. Such binding was abrogated in N‐terminal, but not C‐terminal deletion mutants of STAT1. Furthermore, TgIST did not bind to the STAT1F77Asubstitution mutant that cannot form STAT1 tetramers, resulting in a complete unresponsiveness of parasite‐infected STAT1F77A‐expressing cells to IFN‐γ. Remarkably, binding of TgIST considerably increased the affinity of the aberrant STAT1 tetramers for DNA consensus sequence binding motifs and even enabled binding to nonconsensus sequences. Consistent with the increased DNA binding, STAT1 from parasite‐infected cells remained phosphorylated at Tyr701and Ser727and was retained within the nucleus in a DNA‐bound state. The sustained and promiscuous binding activity particularly of STAT1 tetramers to unspecific DNA sites lacking a consensus STAT1‐binding motif is an as yet unrecognised mechanism contributing to the defective IFN‐γ‐mediated signalling inT. gondii‐infected cells.
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影响因子：
4
作者：
Lüder, CGK;Algner, M;Gross, U
通讯作者：
Gross, U
影响因子：
11.4
作者：
Pattenden, SG;Klose, R;Bremner, R
通讯作者：
Bremner, R
组蛋白脱乙酰酶抑制剂 MS-275 增强弓形虫感染巨噬细胞中 IFN-γ 调节基因子集的表达，但不能改善寄生虫控制
影响因子：
2.1
作者：
Downie;Salinas;Lüder;C.G.K.
通讯作者：
C.G.K.
影响因子：
6.4
作者：
HOWE, DK;SIBLEY, LD
通讯作者：
SIBLEY, LD
影响因子：
5.4
作者：
Lüder, CGK;Walter, W;Gross, U
通讯作者：
Gross, U