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Effects of the Pseudorabies Virus US3 Protein Kinase on Actin and Actin-Controlling Proteins

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Effects of the Pseudorabies Virus US3 Protein Kinase on Actin and Actin-Controlling Proteins Universiteit Gent Faculteit Diergeneeskunde Vakgroep Virologie, Parasitologie en Immunologie Effects of the pseudorabies virus US3 protein kinase on actin and actin-controlling proteins Thary Jacob Proefschrift voorgedragen tot het behalen van de graad van Doctor in de Diergeneeskundige Wetenschappen, 2015 Promotor: Prof. dr. H. Favoreel ISBN: 9789058644459 © 2015 The author and the promoters give the authorization to consult and copy parts of this work for personal use only. Every other use is subject to copyright laws. The author should obtain written permission to reproduce any material contained in this work. Thary Jacob is supported by a personal PhD grant from the Agency for Innovation by Science and Technology in Flanders (IWT-Vlaanderen). This research was supported by a grant from the F.W.O.- Vlaanderen (Grant G.0835.09) and the Research Council of Ghent University (Concerted Research Action 01G01311). About the cover The front cover shows LifeAct (red) transduced swine testicle cells that were transfected with a plasmid encoding PRV US3. US3 protein was stained with primary mouse anti-US3 antibody and secondary FITC-labeled (green) anti-mouse antibody. Nuclei were counterstained with Hoechst 33342 (cyan). This image was taken using a Leica TCS SPE confocal microscope (XY length: 174.6 x 174.6 µm; Z = 6,8 µm, objective: ACS APO 63.0 x 1.30 (oil)). “What is written without effort is, in general, read without pleasure.” - Samuel Johnson Table of contents Abbreviation list .......................................................................................................................... iii Chapter 1: Introduction ................................................................................................................ 1 1. Pseudorabies virus (PRV) ............................................................................................................. 1 1.1 Introduction ......................................................................................................................... 1 1.2 Structure .............................................................................................................................. 2 1.3 Replication cycle .................................................................................................................. 5 1.4 PRV cell-associated spread .................................................................................................. 9 1.5 Aujeszky’s disease ............................................................................................................. 10 1.6 PRV as a model organism to study alphaherpesvirus biology ........................................... 12 2. US3............................................................................................................................................. 14 2.1 Introduction ....................................................................................................................... 14 2.2 Functions ........................................................................................................................... 15 3. The actin cytoskeleton and Rho GTPases .................................................................................. 23 3.1 Introduction ....................................................................................................................... 23 3.2 Composition ...................................................................................................................... 24 3.3 Actin filament-based structures ........................................................................................ 25 3.4 Rho GTPase signaling ......................................................................................................... 28 3.5 Downstream effectors of Rho GTPase signaling that regulate actin polymerization ....... 35 4. Alphaherpesvirus interactions with the actin cytoskeleton and Rho GTPases during virus entry and egress.......................................................................................................................................... 42 4.1 Entry/Transport to the nucleus ......................................................................................... 42 4.2 Egress ................................................................................................................................. 43 5. References ................................................................................................................................. 46 Chapter 2: Aims .......................................................................................................................... 73 Chapter 3: Pseudorabies virus US3 triggers RhoA phosphorylation to reorganize the actin cytoskeleton .............................................................................................................................. 77 Chapter 4: Alphaherpesviral US3 kinase induces cofilin dephosphorylation to reorganize the actin cytoskeleton .............................................................................................................................. 97 Chapter 5: Pseudorabies virus US3 leads to filamentous actin disassembly and contributes to viral genome delivery to the nucleus ................................................................................................. 115 i Chapter 6: General discussion .................................................................................................... 133 Summary .................................................................................................................................. 157 Samenvatting ............................................................................................................................ 163 Curriculum Vitae ....................................................................................................................... 169 Dankwoord ............................................................................................................................... 173 ii Abbreviation list ABP actin binding protein ADF actin depolymerizing factor cAMP cyclic AMP CF corneal fibroblasts CHO Chinese hamster ovary CHX cycloheximide CIN chronophin CRIB cdc42/Rac-interactive binding protein CTL cytotoxic T-lymphocyte CytD cytochalasin D DAD diaphanous-autoregulatory domain DIP diaphanous-interacting protein Drf diaphanous-related formins dTDP deoxythymidine diphosphate dTMP deoxythymidine monophosphate dTTP deoxythymidine triphosphate dUTP deoxyuracyl triphosphate ED equine dermal EHV-1 equine herpesvirus 1 F-actin filamentous actin FH formin homology domain G-actin globular actin GAP GTPase activating protein GBD GTPase binding domain GDI guanine nucleotide dissociation inhibitor iii GDP guanoside diphosphate GTP guanoside triphosphate HDAC histone deacetylase HSV-1 herpes simplex virus 1 HSV-2 herpes simplex virus 2 ICTV International Committee on Taxonomy of Viruses IFN interferon ILTV infectious laryngotracheitis virus IRS internal repeat sequence ISG interferon stimulating gene JMY junction-mediating and regulatory protein KO knock out LIMK LIM (Lin-11, Isl1 and Mec-3) kinase MDCK Madin-Darby canine kidney mDia mammalian homolog of diaphanous MDV Marek's disease virus MEF mouse embryonic fibroblast MHC major histocompatibility complex MLC myosin light chain Nap1 Nck-associated protein 1 NEC herpesviral nuclear egress complex NPF nucleation promoting factor ORF open reading frame PAK p21-activated kinase PAM pulmonary alveolar macrophage PAMP pathogen-associated molecular pattern iv PBD p21-binding domain PDCD4 programmed cell death protein 4 PI(4,5)P2 phosphatidylinositol-4,5-bis-phosphate PK-15 porcine kidney 15 PKA protein kinase A PRR pattern-recognition receptor PRV pseudorabies virus RK13 rabbit kidney 13 ROCK rho associated protein kinase ST swine testicle SuHV1 suid herpesvirus 1 TCR T-cell receptor TESK testicular kinase TRS terminal repeat sequence VCA verprolin homology domain, cofilin homology domain and acidic region VSV vesicular stomatitis virus VZV varicella zoster virus WASH WASP and SCAR homolog WASP Wiskott-Aldrich syndrome protein WAVE WASP family verprolin-homologous protein WH2 WASP homology 2 domain or verprolin homology domain WHAMM WASP homolog associated with actin, membranes, and microtubules WIP WASP interacting protein WISH WASP-interacting SH3-protein WT wild type v Chapter 1 Introduction Introduction Chapter 1: Introduction 1. Pseudorabies virus (PRV) 1.1 Introduction Pseudorabies virus (PRV), also known by its taxonomic name suid herpesvirus 1 (SuHV1) or its original name Aujeszky’s disease virus belongs to the family of the Herpesviridae, subfamily Alphaherpesvirinae, genus Varicellovirus and is the causative agent of Aujeszky’s disease in pigs. Based on their biological properties, genome content and organization, most herpesviruses can be categorized into one of three major subfamilies: Alphaherpesvirinae, Betaherpesvirinae and Gammaherpesvirinae. These subfamilies vary in host range, the cell type where virus latency is established, and duration of the viral replication cycle (Pellet & Roizman, 2007). The broadest host range is displayed by the alphaherpesviruses, which are characterized by a fast replication cycle in host cells, producing viral particles in a matter of hours. For most alphaherpesviruses, latency is established in sensory ganglia. Betaherpesviruses have the most restricted host range and slowest rate of replication. Latency is induced
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