Viral and cellular proteins containing FGDF motifs bind G3BP to block stress granule formation.
Viral and cellular proteins containing FGDF motifs bind G3BP to block stress granule formation.
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DOI：
10.1371/journal.ppat.1004659
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发表时间：
2015-02
期刊：
影响因子：
6.7
通讯作者：
McInerney GM
中科院分区：
文献类型：
--
作者：
Panas MD;Schulte T;Thaa B;Sandalova T;Kedersha N;Achour A;McInerney GM
Ras-GAP SH 3结构域结合蛋白（G3 BP）是在细胞应激（例如病毒感染）时诱导的应激颗粒（SG）、蛋白质和RNA的胞质聚集体的形成的重要调节剂。许多病毒，包括塞姆利基森林病毒（SFV），通过靶向G3 BP阻断SG诱导。在这项工作中，我们证明了SFV nsP 3的G3 BP结合基序由两个FGDF基序组成，其中苯丙氨酸和甘氨酸残基是必不可少的结合。此外，我们表明，细胞G3 BP结合伴侣USP 10的结合也是由FGDF基序介导的。wt USP 10的过表达（而不是缺乏FGDF基序的突变体）会阻止SG组装。此外，我们鉴定了单纯疱疹病毒（HSV）蛋白ICP 8中FGDF介导的G3 BP结合位点，并表明ICP 8与G3 BP结合也抑制SG形成，这是HSV ICP 8的新功能。我们提出了一个模型的三维结构的G3 BP绑定到一个含FGDF的肽，可能代表了许多蛋白质共享的结合模式，以目标G3 BP。应激颗粒（Stress granules，SG）是在各种应激条件（如病毒感染）下在细胞中形成的蛋白质和自发沉默的mRNA的动态聚集体。SG被认为是抗病毒的，因此许多病毒已经进化出对策来防止它们的形成，通常针对必需的SG蛋白G3 BP。在这里，我们发现几种其他无关的病毒和细胞蛋白都与序列基序FGDF结合G3 BP，从而抑制SG形成：旧世界甲病毒Semliki森林病毒的非结构蛋白3（nsP 3）（一种新出现的高致病性基孔肯雅病毒的近亲）;单纯疱疹病毒的蛋白质ICP 8;此外，细胞蛋白USP 10（SG组分和蛋白质去泛素酶，其稳定例如肿瘤抑制因子p53）。在这项工作中，我们还提出并验证了一个模型的三维结构的G3 BP绑定到一个含FGDF的肽。FGDF介导的G3 BP结合代表了针对一系列不同病毒感染的治疗干预的有吸引力的靶标，并且还可以调节USP 10在癌症中的p53稳定功能。
The Ras-GAP SH3 domain–binding proteins (G3BP) are essential regulators of the formation of stress granules (SG), cytosolic aggregates of proteins and RNA that are induced upon cellular stress, such as virus infection. Many viruses, including Semliki Forest virus (SFV), block SG induction by targeting G3BP. In this work, we demonstrate that the G3BP-binding motif of SFV nsP3 consists of two FGDF motifs, in which both phenylalanine and the glycine residue are essential for binding. In addition, we show that binding of the cellular G3BP-binding partner USP10 is also mediated by an FGDF motif. Overexpression of wt USP10, but not a mutant lacking the FGDF-motif, blocks SG assembly. Further, we identified FGDF-mediated G3BP binding site in herpes simplex virus (HSV) protein ICP8, and show that ICP8 binding to G3BP also inhibits SG formation, which is a novel function of HSV ICP8. We present a model of the three-dimensional structure of G3BP bound to an FGDF-containing peptide, likely representing a binding mode shared by many proteins to target G3BP. Stress granules (SGs) are dynamic aggregates of proteins and translationally silenced mRNA that are formed in cells upon various stress conditions, such as virus infection. SGs are thought to be antiviral, and many viruses have hence evolved countermeasures to prevent their formation, often targeting the essential SG protein G3BP. Here, we show that several otherwise unrelated viral and cellular proteins all bind G3BP with the sequence motif FGDF, and thereby repress SG formation: the non-structural protein 3 (nsP3) of the Old World alphavirus Semliki Forest virus (a close relative of the emerging, highly pathogenic Chikungunya virus); the protein ICP8 of herpes simplex virus; and in addition, the cellular protein USP10 (an SG component and protein deubiquitinase that stabilises e.g. the tumor suppressor p53). In this work, we also present and validate a model of the three-dimensional structure of G3BP bound to an FGDF-containing peptide. The FGDF-mediated G3BP binding represents an attractive target for therapeutic interventions against a range of diverse viral infections, and may also regulate the p53-stabilising function of USP10 in cancers.
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