{"doi":"10.7302/25552","title":"Mechanistic Insights into How a DNA and RNA Virus Hijack the Cellular Secretory Pathway to Cause Infection","abstract":"The cellular secretory pathway is an organized system that compartmentalizes the factors necessary for protein biosynthesis, modification, sorting, and release. Composed of the endoplasmic reticulum (ER), the Golgi apparatus (Golgi), the endosomal membranes (endosomes), and the plasma membrane, the secretory pathway allows for bidirectional movement across the cell so that cellular components (including proteins and lipids) can move from the ER to the plasma membrane or in the opposite direction. Strikingly, this bidirectional secretory pathway can be exploited by viruses, whether it is a DNA or an RNA virus, to cause infection. This dissertation examines the mechanisms by which the Dengue virus (DENV), an RNA virus, hijacks the ER function, and the human papillomavirus (HPV), a DNA virus, co-opts the Golgi function, in order to promote infection. During entry, DENV reaches the endosome after receptor-mediated endocytosis. The virus releases its genome into the cytoplasm through fusion of the viral envelope to the late endosome membrane. The viral genome is then delivered to the ER where the viral polyprotein - composed of structural and nonstructural (NS) proteins - is synthesized through co-translational translocation. Biosynthesis of the viral structural and NS proteins is required for productive infection. Here we show that EMC4, one subunit of the multi-subunit ER membrane complex, promotes the fusion of the viral envelope to the late endosome membrane. Specifically, EMC4 facilitates transfer of phosphatidylserine from the ER to the late endosome whose presence in the endosome is known to be critical for mediating fusion between the viral and endosome membranes. After endocytosis, HPV reaches the endosome and is trafficked to the trans Golgi network (TGN) and Golgi membranes before mobilizing to the nucleus for replication. In the endosome, the HPV minor capsid protein L2 inserts across the membrane and becomes exposed to the cytosol. The overarching model postulates that the cytosol-exposed region of L2 recruits different host factors to transport the virus along the endosome->TGN/Golgi membrane->nucleus productive route. My thesis identifies the BICD2-dynein complex as the necessary motor to drive transport of HPV across the endosome->TGN/Golgi membrane->nucleus pathway leading to infection. The BICD2 dynein cargo adaptor binds directly to L2 and recruits dynein to the virus for trafficking. Additionally, we propose that the Golgi-localized, transmembrane protein YIPF3 binds to and promotes HPV infection. In sum, the chapters of this dissertation demonstrate how basic cell biology can be taken advantage of by viruses to carry out infection. Despite the differences in entry pathways, both DNA and RNA viruses can utilize the locally-concentrated host factors in overlapping organelles to successfully enter and infect the cell.","journal":"Deep Blue (University of Michigan)","year":2025,"id":575531,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9511,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":337921,"name":"Kaitlyn Speckhart","orcid":"0000-0002-6821-1352","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:57:48.486077Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}