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PLoS Pathog:阻断寄生虫GCN5b酶对抗弓形虫病

来源:生物谷 2014-01-05 14:37

2014年1月4日讯 /生物谷BIOON/--近日,美国印第安纳大学医学院研究人员新发现的蛋白质GCN5b酶可能成为新的药物靶标来控制引起弓形虫病的寄生虫。这一发现还可能开辟新的途径治疗疟疾。

研究人员确定了蛋白质GCN5b酶是必要的弓形体寄生虫复制,因此GCN5b酶活动的干扰可以控制寄生虫。GCN5b是寄生虫中开启和关闭基因的分子机制的一部分,研究人员发现,GCN5b是一种植物类转录因子。

药理学和毒理学副教授说William J. Sullivan Jr表示:比在人类中存在的对应蛋白相比,GCN5b是一个非常不同的蛋白质,与其作用的蛋白质并没有在人类中发现。研究发现一些与GCN5b相互作用的蛋白质是植物类转录因子,新研究揭示了寄生虫如何控制开启和关闭基因过程中一直缺失的环节。

植物类转录因子募集GCN5b酶复合物,激活多种基因的表达。当研究小组阻断GCN5b复合物,寄生虫​​复制迅速被抑制。Sullivan博士和他的同事在PLOS Pathogens杂志上报告了他们的发现。

在美国。很多人感染了弓形虫寄生虫,但在大多数情况下,感染会产生类似流感的症状或没有症状。但是,对于免疫系统疾病患者如接受化疗或艾滋病人,这种疾病可引起严重的后果,包括肺问题,视力模糊和癫痫发作。

虽然有抗寄生虫药物可用于治疗弓形虫病急性发作,它目前不可能完全消除这种寄生虫,因为它可以在体内从一个活跃状态转换到一个潜在休眠状态。由于GCN5b在急性和潜伏阶段都处于活跃状态,GCN5b酶及其相关联的组件是非常有前途的候选药物靶标。(生物谷Bioon.com)

Lysine Acetyltransferase GCN5b Interacts with AP2 Factors and Is Required for Toxoplasma gondii Proliferation

Hiroyasu Yamamoto, Evan G. Williams, Laurent Mouchiroud, Carles Cantó, Weiwei Fan, Michael Downes, Christophe Héligon, Grant D. Barish, Béatrice Desvergne, Ronald M. Evans et al.

Histone acetylation has been linked to developmental changes in gene expression and is a validated drug target of apicomplexan parasites, but little is known about the roles of individual histone modifying enzymes and how they are recruited to target genes. The protozoan parasite Toxoplasma gondii (phylum Apicomplexa) is unusual among invertebrates in possessing two GCN5-family lysine acetyltransferases (KATs). While GCN5a is required for gene expression in response to alkaline stress, this KAT is dispensable for parasite proliferation in normal culture conditions. In contrast, GCN5b cannot be disrupted, suggesting it is essential for Toxoplasma viability. To further explore the function of GCN5b, we generated clonal parasites expressing an inducible HA-tagged dominant-negative form of GCN5b containing a point mutation that ablates enzymatic activity (E703G). Stabilization of this dominant-negative GCN5b was mediated through ligand-binding to a destabilization domain (dd) fused to the protein. Induced accumulation of the ddHAGCN5b(E703G) protein led to a rapid arrest in parasite replication. Growth arrest was accompanied by a decrease in histone H3 acetylation at specific lysine residues as well as reduced expression of GCN5b target genes in GCN5b(E703G) parasites, which were identified using chromatin immunoprecipitation coupled with microarray hybridization (ChIP-chip). Proteomics studies revealed that GCN5b interacts with AP2-domain proteins, apicomplexan plant-like transcription factors, as well as a “core complex” that includes the co-activator ADA2-A, TFIID subunits, LEO1 polymerase-associated factor (Paf1) subunit, and RRM proteins. The dominant-negative phenotype of ddHAGCN5b(E703G) parasites, considered with the proteomics and ChIP-chip data, indicate that GCN5b plays a central role in transcriptional and chromatin remodeling complexes. We conclude that GCN5b has a non-redundant and indispensable role in regulating gene expression required during the Toxoplasma lytic cycle.

 

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