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  • 1.
    Broniarczyk, Justyna
    et al.
    Department of Molecular Virology, Adam Mickiewicz University.
    Wigerius, Michael
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi. Södertörns högskola, Institutionen för livsvetenskaper, Kemi.
    Johansson, Magnus
    Södertörns högskola, Institutionen för livsvetenskaper, Internationell hälsa. Södertörns högskola, Institutionen för livsvetenskaper, Kemi.
    The NS1 protein of Influenza A virus targets human Scribble in asubtype specific mannerManuskript (preprint) (Annet vitenskapelig)
  • 2.
    Melik, Wessam
    et al.
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi. Södertörns högskola, Institutionen för livsvetenskaper, Kemi.
    Ellencrona, Karin
    Södertörns högskola, Institutionen för livsvetenskaper.
    Wigerius, Michael
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi. Södertörns högskola, Institutionen för livsvetenskaper, Kemi.
    Elväng, Annelie
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi.
    Hedström, Chister
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi.
    Johansson, Magnus
    Södertörns högskola, Institutionen för livsvetenskaper, Internationell hälsa. Södertörns högskola, Institutionen för livsvetenskaper, Kemi.
    Two PDZ binding motifs within NS5 have roles in Tick-borne encephalitis virus replication2012Inngår i: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 169, nr 1, s. 54-62Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The flavivirus genus includes important human pathogens like Tick-borne encephalitis virus (TBEV), Dengue virus (DV) and West-Nile virus (WNV), that can cause severe disease e.g. encephalitis or hemorrhagic fever. The NS5 protein is a multifunctional RNA dependent RNA polymerase indispensable for the flavivirus replication. We have previously shown that TBEVNS5 contains a unique internal PDZ binding motif (YS223) for specific targeting of the PDZ protein Scribble. This interaction has impact on both viral down regulation of host cellular defense systems and neurite outgrowth. Putative C-terminal PDZ binding motifs present in TBEVNS5 (-SII903) and WNVNS5 (-TVL905) have also previously been highlighted.

    To determine whether the PDZ binding motifs of TBEVNS5 has an effect on virus replication we constructed a DNA based sub-genomic TBEV replicon expressing firefly luciferase. The motifs within NS5 were mutated individually and in concert and the replicons were assayed in cell culture. Our results show that the replication rate was impaired in all mutants, which indicates that PDZ dependent host interactions influence flavivirus replication.We also find that the C-terminal PDZ binding motif present in TBEVNS5 and WNVNS5 are targeting various human PDZ domain proteins. TBEVNS5 has high affinity to Zonulaoccludens-2 (ZO-2),GIAP C-terminus interacting protein (GIPC), Calcium/calmodulin-dependent serine protein kinase (CASK) and Interleukin 16 (IL-16).A different pattern was observed for WNVNS5 as it associated with IL-16, and several other putative interaction partners.

  • 3.
    Werme, Karin
    et al.
    Södertörns högskola, Institutionen för livsvetenskaper. Stockholm University.
    Wigerius, Michael
    Södertörns högskola, Institutionen för livsvetenskaper. Stockholm University.
    Johansson, Magnus
    Södertörns högskola, Institutionen för livsvetenskaper.
    Tick-borne encephalitis virus NS5 associates with membrane protein scribble and impairs interferon-stimulated JAK-STAT signalling.2008Inngår i: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 10, nr 3, s. 696-712Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tick-borne encephalitis virus (TBEV) NS5 protein is a multifunctional RNA-dependent RNA polymerase that is indispensable for viral replication. TBEV is considered to be highly neurovirulent and can cause lethal encephalitis. In this study, we demonstrate a novel interaction between TBEV NS5 and the PDZ protein scribble (hScrib) affecting interferon (IFN) type I and II mediated JAK-STAT signalling. The sequence of TBEV NS5 interacting with hScrib was identified using extensive site-directed mutagenesis analysis. Two consecutive mutations in the methyltransferase (MTase) domain of NS5 were found to disrupt binding to hScrib. Colocalization studies with hScrib demonstrated that TBEV NS5 was present at the plasma membrane of mammalian cells. To address the role of viral interference with the IFN response, NS5 proteins were expressed in IFN-stimulated cells. While TBEV NS5 substantially blocked phosphorylation of STAT1, a mutated NS5 protein defective in hScrib binding failed to inhibit JAK-STAT signalling correctly. Furthermore, hScrib knock-down resulted in re-localization of NS5 to intracellular locations and abrogated the impaired STAT1 phosphorylation. These results define the TBEV NS5 protein in concert with hScrib as an antagonist of the IFN response, by demonstrating a correlation between the association and JAK-STAT interference.

  • 4.
    Wigerius, Michael
    Södertörns högskola, Institutionen för livsvetenskaper, Kemi. Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi.
    Roles of mammalian Scribble in polarity signaling, virus offense and cell-fate determination2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Mammalian Scribble is a target for proteins encoded by human papilloma virus, retro- and flaviviruses. Tick-borne encephalitis virus (TBEV) is a flavivirus that have evolved distinct strategies to escape antiviral responses. Information of how flaviviruses intrude on cell integrity comes from understanding of the roles that host-factors play when they interfere with viruses. The first part of this thesis describes a novel interaction between the TBEVNS5 protein and Scribble. The importance of the interaction was demonstrated by RNAi-mediated depletion of Scribble, which prevented suppression of JAK-STAT signaling by NS5. Together, these results define Scribble as a novel target for NS5.

    TBEV is known to cause central nervous system disease TBE in humans that can lead to cognitive dysfunction. A unifying theme in CNS related diseases are defects in neuronal extensions. We therefore addressed the effects of TBEV expression in PC12 cell differentiation, which is characterized by extensive neurite growth. Our data show that TBEVNS5 suppresses neurite outgrowth through the Rho GTPase Rac1. These findings provide evidence that Rac1 is an indirect target of NS5 in neurite inhibition. Scribble was recently implicated in spine morphogenesis. Thus, we tested the role of Scribble in neurite elongation. Depletion of Scribble in PC12 cells, reduced neurite density but increased length of those remaining. Moreover, Scribble bound components in the Ras/ERK cascade in a growth factor dependent manner. Together, these results demonstrate that Scribble controls neurite elongation by scaffolding MAPK components. Moreover, as loss of dendritic spines, actin-rich protrusions on neurons, is a feature in cognitive dysfunction we speculate that cognitive dysfunction in TBE might involve disturbed Scribble expression by NS5.

    We also investigated the binding between NS1 of Influenza A virus and Scribble. The PDZ domains of Scribble are usually selective for specific C-terminal motifs in proteins. Because NS1 has a canonical PDZ motif we tested if binding to Scribble depends on this motif. We found that Scribble binds NS1; the association is dependent on the NS1 C-terminus that is recognized by PDZ3-4 of Scribble. Together, these results suggest that Scribble is a target for the H5N1 NS1 protein 

  • 5.
    Wigerius, Michael
    et al.
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi. Dalhousie University.
    Asghar, Naveed
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi.
    Melik, Wessam
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi.
    Johansson, Magnus
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi. Örebro university.
    Scribble controls NGF-mediated neurite outgrowth in PC12 cells2013Inngår i: European Journal of Cell Biology, ISSN 0171-9335, E-ISSN 1618-1298, Vol. 92, nr 6-7, s. 213-221Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neurite outgrowth is mediated by dynamic changes of the cytoskeleton and is largely controlled by Rho GTPases and their regulators. Here, we show that the polarity protein Scribble controls PC12 cell neurite outgrowth in response to nerve growth factor. Scribble knockdown decreases neurite numbers and increases neurite length. This effect is linked to TrkA the cognate receptor for NGF as pharmacological inhibition of phosphorylated TrkA (pTrkA) reduces Scribble expression. Moreover, Scribble forms a complex with the MAPK components ERK1/2 in a growth factor dependent manner. In RNAi experiments where Scribble expression is efficiently depleted sustained ERK1/2 phosphorylation is reduced. Conversely, siRNA with intermediate Scribble silencing efficiency fails to match this effect indicating that ERK1/2 activation depends on basic Scribble protein levels. Finally, Scribble translocates to the plasma membrane in response to growth factor where it complexes with HRas and Rac1 suggesting that the phenotype activated by loss of Scribble may be a result of altered GTPase activity. Together, these results demonstrate a novel role for Scribble in neurite outgrowth of PC12 cells.

  • 6.
    Wigerius, Michael
    et al.
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi. Södertörns högskola, Institutionen för livsvetenskaper, Kemi.
    Johansson, Magnus
    Södertörns högskola, Institutionen för livsvetenskaper, Internationell hälsa. Södertörns högskola, Institutionen för livsvetenskaper, Kemi.
    SCRIBBLE SCAFFOLDS KEY COMPONENTS IN NEURITE OUTGROWTHIMPLICATING DIRECT INVOLVEMENT IN CYTOSKELETON REGULATIONManuskript (preprint) (Annet vitenskapelig)
  • 7.
    Wigerius, Michael
    et al.
    Södertörns högskola, Institutionen för livsvetenskaper, Kemi. Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi.
    Melik, Wessam
    Södertörns högskola, Institutionen för livsvetenskaper, Kemi. Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi.
    Elväng, Annelie
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi.
    Johansson, Magnus
    Södertörns högskola, Institutionen för livsvetenskaper, Kemi. Södertörns högskola, Institutionen för livsvetenskaper, Internationell hälsa.
    Rac1 and Scribble are targets for the arrest of neurite outgrowth by TBE virus NS52010Inngår i: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 44, nr 3, s. 260-271Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    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, beta PIX 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 beta PIX 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.

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