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Open Lochmann-Dissertation-Final The Pennsylvania State University The Graduate School College of Medicine A JOURNEY TO THE CENTER OF THE CELL: INSIGHTS INTO SUBNUCLEAR TRAFFICKING OF THE ROUS SARCOMA VIRUS GAG POLYPROTEIN A Dissertation in Genetics by Timothy Lewis Lochmann Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy December 2011 The dissertation of Timothy Lewis Lochmann was reviewed and approved* by the following: Leslie J. Parent Associate Professor of Medicine, and Microbiology and Immunology Dissertation Adviser Chair of Committee David J. Spector Professor of Microbiology Member of the Genetics Executive Committee Jianming Hu Professor of Microbiology and Immunology Sergei A. Grigoryev Associate Professor of Biochemistry and Molecular Biology Christopher Herzog Assistant Professor of Pharmacology *Signatures are on file in the Graduate School. ii Abstract The assembly of retrovirus particles is directed by the retroviral Gag polyprotein. The Rous sarcoma virus (RSV) Gag polyprotein is synthesized in the cytoplasm. During the early steps of assembly, Gag undergoes transient nuclear trafficking mediated by nuclear localization signals (NLSs) in the matrix (MA) and nucleocapsid (NC) domains, and a nuclear export signal (NES) present within the p10 domain. Gag nuclear trafficking has been linked to efficient packaging of viral genomic RNA. However, whether Gag undergoes intranuclear trafficking and what host factors Gag may interact with in the nucleus remains poorly understood. The ability to mutate the NES and inhibit nuclear export makes RSV a useful model to study the roles of Gag within the nucleus and how Gag interacts with nuclear factors during retrovirus infection. Experiments aimed at identifying Gag-Gag interactions within the nucleus revealed that Gag proteins accumulated within punctate nuclear foci. These subnuclear foci were not virus-like particles forming within the nucleus. The formation of Gag-containing foci was dependent upon the presence of NC, which is an RNA binding domain. Further studies revealed that Gag nuclear puncta were anchored within the nucleoplasm at discrete locations, but individual Gag molecules move between the subnuclear structures and the nucleoplasm. These results suggest that the Gag proteins are retained at a particular subnuclear structure, perhaps being anchored there by an interaction with a cellular protein or RNA molecule. In addition to nucleoplasmic foci, Gag also accumulated within nucleoli in an NC- dependent manner. Similar to the nuclear puncta, Gag proteins moved in and out of nucleoli. Using site-directed mutagenesis, the amino acids involved in nucleolar localization of NC were identified. Furthermore, mutations that eliminated nucleolar localization of NC also prevented Gag from accumulating within nucleoli. These results indicate that NC plays a key role in the nucleolar localization and subnuclear trafficking of the Gag protein. iii However, whether these nuclear accumulations of Gag serve a purpose during viral replication is unknown. To determine whether nucleolar localization was involved in retroviral replication, proviral vectors were used to examine how mutations to the basic residues within NC affected virus particle release, gRNA packaging, and infectivity. In general, mutations that reduced NC nucleolar localization did not affect particle release, but gRNA packaging and infectivity were impaired in some viral mutants. The presence of a minimal number of positively charged residues within NC is not linked to gRNA packaging, although the location of the basic residues was important. Elimination of NC nucleolar localization reduced the ability of the virus to spread in infectivity assays. Together, these results suggest that NC nucleolar localization is important for infectivity, but not gRNA packaging or virus particle release. To further examine the role of nucleoli in retroviral infection, a gain-of-function approach was used. A heterologous nucleolar localization signal (NoLS), from either the HIV-1 Rev protein or the HSV ICP27 protein, was inserted into an NC mutant deficient in nucleolar localization. In addition to being NoLSs, both the Rev and ICP27 sequences were also RNA-binding domains (RBDs). Both sequences were able to restore NC nucleolar localization, and the presence of these heterologous sequences caused nucleolar accumulation of Gag without a nuclear export mutation. Surprisingly, although the nucleolar localization signal from ICP27 did not hinder viral assembly, the NoLS from Rev greatly decreased viral budding. Both NoLSs/RBD restored incorporation of gRNA into virus particles. However, a virus containing either NoLS was noninfectious. These data demonstrate that insertion of a heterologous NoLS/RBD binding domain is sufficient to restore incorporation of gRNA to a packaging deficient virus. iv Table of Contents List of Figures ..................................................................................................................... vii List of Tables ...................................................................................................................... viii Abbreviation list ................................................................................................................... ix Acknowledgements ............................................................................................................. xi Chapter 1: Literature review ................................................................................................ 1 1.1 Introduction to dissertation ................................................................................ 2 1.2 Classification of retroviruses and genome organization ................................ 4 1.3 Organization of retroviral particles ................................................................... 8 1.4 Early events of the retroviral life cycle ........................................................... 11 1.4.1 Attachment, fusion, and entry ............................................................... 11 1.4.2 Uncoating and reverse transcription ..................................................... 14 1.4.3 Nuclear entry of the PIC ....................................................................... 15 1.4.4 Integration of the viral DNA .................................................................. 16 1.5 Late events of the retroviral life cycle ............................................................. 16 1.5.1 Transcription and splicing of viral RNA ................................................. 16 1.5.2 Nuclear export of viral RNA .................................................................. 19 1.5.3 Translation of viral proteins .................................................................. 20 1.5.4 Assembly of immature virus ................................................................. 20 1.5.5 RNA packaging ..................................................................................... 22 1.5.5.1 Packaging of viral RNA .......................................................... 22 1.5.5.2 Packaging of cellular RNA ..................................................... 23 1.5.6 Budding ................................................................................................ 25 1.5.7 Maturation ............................................................................................. 26 1.6 Nuclear trafficking of the RSV Gag polyprotein ............................................. 26 1.7 The many roles of the retroviral nucleocapsid (NC) ...................................... 28 1.7.1 Structure and function of NC ................................................................ 28 1.7.2 Role of NC in viral entry ........................................................................ 33 1.7.2.1 NC and reverse transcription ................................................. 33 1.7.2.2 Role of NC in PIC nuclear entry ............................................. 34 1.7.3 Role of NC in viral assembly ................................................................ 35 1.7.4 Role of NC in gRNA packaging ............................................................ 37 1.7.4.1 NC zinc fingers ...................................................................... 37 1.7.4.2 NC basic residues .................................................................. 38 1.8 The nucleolus .................................................................................................... 39 1.8.1 Signals and mechanisms of nucleolar trafficking ................................. 42 1.8.2 Viruses and nucleoli ............................................................................. 47 1.9 Live cell imaging techniques ........................................................................... 50 1.9.1 Fluorescence recovery after photobleaching (FRAP) .......................... 51 1.9.2 Fluorescence resonance energy transfer (FRET) ................................ 54 1.10 Conclusion ....................................................................................................... 59 Chapter 2: Characterization of Subnuclear Foci Formed by Gag proteins Restricted to the Nucleus .......................................................................................................................... 61 2.1 Abstract .............................................................................................................. 62 2.2 Introduction ......................................................................................................
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