This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedĭata Availability: All relevant data are within the paper and its Supporting Information files.įunding: This research was supported by a Cancerfonden (Swedish Cancer Society) Project grant (CF 2012/789) to GMM. Received: SeptemAccepted: JanuPublished: February 6, 2015Ĭopyright: © 2015 Panas et al. Heise, University of North Carolina at Chapel Hill, UNITED STATES (2015) Viral and Cellular Proteins Containing FGDF Motifs Bind G3BP to Block Stress Granule Formation. 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.Ĭitation: Panas MD, Schulte T, Thaa B, Sandalova T, Kedersha N, Achour A, et al. In this work, we also present and validate a model of the three-dimensional structure of G3BP bound to an FGDF-containing peptide. 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. SGs are thought to be antiviral, and many viruses have hence evolved countermeasures to prevent their formation, often targeting the essential SG protein 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. 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. 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. Overexpression of wt USP10, but not a mutant lacking the FGDF-motif, blocks SG assembly. In addition, we show that binding of the cellular G3BP-binding partner USP10 is also mediated by an FGDF motif. 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. Many viruses, including Semliki Forest virus (SFV), block SG induction by targeting G3BP. 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.
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