title: Rac1 and Scribble are targets for the arrest of neurite outgrowth by TBE virus NS5.
abstract: Tick-borne encephalitis virus (TBEV) causes extensive CNS disease in humans known as TBE, however, relatively little is known of the molecular mechanisms for its progress. Here, we now show that TBEV produces defects in neuronal development of PC12 cells through a function of the viral NS5 protein. The methyltransferase domain of NS5 is critical and sufficient for restriction of nerve growth factor induced neurite outgrowth. This effect is reversed by expression of NS5 mutants unable to bind Scribble and unexpectedly, in Scribble depleted cells with binding-competent NS5. Furthermore, we also demonstrate that the Rho GTPase Rac1 and the guanine nucleotide-exchange factor, betaPIX are outcompeted by NS5 for binding to Scribble, linking to effects on neurite outgrowth by TBEV. Together, these findings provide the first experimental evidence that Rac1 and betaPIX are indirect targets of NS5 acting through the multifunctional polarity protein Scribble to oppose neuronal differentiation. In conclusion, our results offer a potential mechanism by which TBEV alters neuronal circuitry and opens new avenues for therapeutic interventions.
authors.affiliation: School of Life Sciences, Södertörn University, SE-141 89 Huddinge, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Wigerius
authors.forename: Wessam
authors.initials: W
authors.lastname: Melik
authors.forename: Annelie
authors.initials: A
authors.lastname: Elväng
authors.forename: Magnus
authors.initials: M
authors.lastname: Johansson
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D004669:Encephalitis Viruses, Tick-Borne / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016501:Neurites / Q000378:metabolism*; D016716:PC12 Cells; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C096041:NS5 protein, flavivirus; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D025521:Tumor Suppressor Proteins; D017361:Viral Nonstructural Proteins; C548802:scribble protein, rat; D020830:rac1 GTP-Binding Protein