{"@context":"http://iiif.io/api/presentation/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/manifest.json","@type":"sc:Manifest","label":"Regulation of Post-translational Modifications by the Adenovirus E4-ORF3 Protein","metadata":[{"label":"dc.description.sponsorship","value":"This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree"},{"label":"dc.format","value":"Monograph"},{"label":"dc.format.medium","value":"Electronic Resource"},{"label":"dc.identifier.uri","value":"http://hdl.handle.net/11401/78183"},{"label":"dc.language.iso","value":"en_US"},{"label":"dcterms.abstract","value":"Adenovirus (Ad) is a human DNA tumor virus that has been used extensively as a model to understand many fundamental cellular processes and host-pathogen interactions.  During infection, the Ad type 5 (Ad5) early protein, E4-ORF3, forms unique track-like structures throughout nuclei of infected cells.  E4-ORF3 tracks serve to relocalize and sequester many cellular proteins, including Mre11 and Nbs1, two antiviral components of the DNA damage-responsive MRN complex.  Relocalization of Mre11 and Nbs1 to E4-ORF3 tracks facilitates their post-translational modification with the small ubiquitin-like modifier, SUMO.  SUMOylation is essential to the regulation of many cellular processes, including transcription, replication, and DNA repair, and can have diverse substrate-specific effects on proteins.  Since many cellular proteins are recruited to E4-ORF3 tracks, we hypothesized that E4-ORF3 may induce SUMOylation of additional unidentified cellular factors during Ad infection.  The studies detailed herein focus on identifying cellular proteins SUMOylated in an E4-ORF3-dependent manner, describing the functional consequences of E4-ORF3-induced SUMOylation, and characterizing the precise molecular mechanisms regulating these processes.   My studies revealed that E4-ORF3 induces SUMOylation of the general transcription factor, TFII-I, which was previously shown to be a transcriptional repressor of the Ad L4 promoter.  I found that SUMOylation of TFII-I during Ad infection was dependent on its relocalization into E4-ORF3 tracks.  I subsequently found that TFII-I SUMOylation leads to its ubiquitination and proteasome-dependent degradation.  Finally, I focused on identifying the specific cellular factors involved in E4-ORF3-mediated modulation of TFII-I.  My work showed that Ad usurps the activities of two DNA repair factors to aid in the proteolytic processing of TFII-I during infection: RNF4, a SUMO-targeted ubiquitin ligase responsible for ubiquitination of SUMOylated proteins, and VCP/p97, an ATPase that extracts ubiquitinated proteins from large macromolecular structures and mediates their degradation by the ubiquitin-proteasome system. Together, these studies identify TFII-I as a novel target of the Ad5 E4-ORF3 protein and elucidate the functional consequences of E4-ORF3-induced SUMOylation of TFII-I.  My studies show that E4-ORF3-induced SUMOylation leads to proteasome-dependent degradation of restrictive host factors, including TFII-I, and provide in-depth mechanistic insight into how a small viral protein like E4-ORF3 can regulate diverse antiviral processes during infection."},{"label":"dcterms.available","value":"2018-03-22T22:39:15Z"},{"label":"dcterms.contributor","value":"Hearing, Patrick."},{"label":"dcterms.creator","value":"Bridges, Rebecca"},{"label":"dcterms.dateAccepted","value":"2018-03-22T22:39:15Z"},{"label":"dcterms.dateSubmitted","value":"2018-03-22T22:39:15Z"},{"label":"dcterms.description","value":"Department of Molecular Genetics and Microbiology."},{"label":"dcterms.extent","value":"122 pg."},{"label":"dcterms.format","value":"Monograph"},{"label":"dcterms.identifier","value":"http://hdl.handle.net/11401/78183"},{"label":"dcterms.issued","value":"2017-08-01"},{"label":"dcterms.language","value":"en_US"},{"label":"dcterms.provenance","value":"Made available in DSpace on 2018-03-22T22:39:15Z (GMT). No. of bitstreams: 1\nBridges_grad.sunysb_0771E_13411.pdf: 7893995 bytes, checksum: ea71d07771b7199d67d7c5b4480ed53b (MD5)\n  Previous issue date: 2017-08-01"},{"label":"dcterms.subject","value":"E4-ORF3"},{"label":"dcterms.title","value":"Regulation of Post-translational Modifications by the Adenovirus E4-ORF3 Protein"},{"label":"dcterms.type","value":"Dissertation"},{"label":"dc.type","value":"Dissertation"}],"description":"This manifest was generated dynamically","viewingDirection":"left-to-right","sequences":[{"@type":"sc:Sequence","canvases":[{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json","@type":"sc:Canvas","label":"Page 1","height":1650,"width":1275,"images":[{"@type":"oa:Annotation","motivation":"sc:painting","resource":{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/13%2F15%2F77%2F131577676601798769722981869260972199930/full/full/0/default.jpg","@type":"dctypes:Image","format":"image/jpeg","height":1650,"width":1275,"service":{"@context":"http://iiif.io/api/image/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/13%2F15%2F77%2F131577676601798769722981869260972199930","profile":"http://iiif.io/api/image/2/level2.json"}},"on":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json"}]}]}]}