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The NS1 protein of Influenza A virus targets human Scribble in asubtype specific manner
Department of Molecular Virology, Adam Mickiewicz University.
Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi. Södertörns högskola, Institutionen för livsvetenskaper, Kemi.
Södertörns högskola, Institutionen för livsvetenskaper, Internationell hälsa. Södertörns högskola, Institutionen för livsvetenskaper, Kemi.
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Biologiska vetenskaper
Forskningsämne
molekylär cellbiologi
Identifikatorer
URN: urn:nbn:se:sh:diva-14765OAI: oai:DiVA.org:sh-14765DiVA, id: diva2:478635
Tillgänglig från: 2010-05-13 Skapad: 2012-01-16 Senast uppdaterad: 2012-11-01Bibliografiskt granskad
Ingår i avhandling
1. Roles of mammalian Scribble in polarity signaling, virus offense and cell-fate determination
Öppna denna publikation i ny flik eller fönster >>Roles of mammalian Scribble in polarity signaling, virus offense and cell-fate determination
2010 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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 

Ort, förlag, år, upplaga, sidor
Stockolm: Department of Biochemistry and Biophysics, Stockholm University, 2010. s. 45
Serie
Södertörn Doctoral Dissertations, ISSN 1652-7399 ; 47
Nyckelord
cell polarity, scribble, tbev, RhoGTPase, jak-stat, mapk, neurite outgrowth, influenza a virus
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
biokemi
Identifikatorer
urn:nbn:se:sh:diva-14764 (URN)978-91-7447-067-3 (ISBN)978-91-86069-15-5 (ISBN)
Disputation
2010-06-18, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, 10:00 (Engelska)
Opponent
Handledare
Anmärkning

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: In press. Paper 3: Manuscript. Paper 4: Manuscript.

Tillgänglig från: 2012-01-16 Skapad: 2012-01-16 Senast uppdaterad: 2012-10-30Bibliografiskt granskad

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Wigerius, MichaelJohansson, Magnus

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