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Principal Investigator: Samuel K Campos
Organization: UNIVERSITY OF ARIZONA
Fiscal Year: 2021
Award: $332,959
Funding agency: National Institute of General Medical Sciences
Human papillomaviruses (HPVs) are the most common sexually transmitted infection. These viruses infect and replicate in mucosal and cutaneous epithelium, inducing cell proliferation as part of their replicative life cycle. High risk oncogenic HPVs caused over 500,000 cases of cervical cancer worldwide, the fourth most common cancer in women (2012 estimates). HPVs are small DNA viruses and must deliver their genomes to the host cell nucleus to initiate a successful infection. Like all other non-enveloped viruses, HPVs must transport their genetic material (vDNA) across an intracellular limiting membrane, a critical event mediated by the minor capsid protein L2. Our prior work has implicated the N-terminal domain of L2 as a crucial region for this membrane penetration activity. N- terminal cleavage of L2 by the host cell protease furin and a conserved transmembrane domain (TMD) are essential for vDNA translocation. During virion entry, cleavage of L2 by cell surface furin appears to modulate a conformational change enabling L2 to interact and span across local membranes, an activity we call “protrusion”. In this membrane-protruding conformation, L2 is able to access the cytosol to recruit cellular sorting factors while remaining complexed to the lumenal vDNA. Engagement of cytosolic sorting nexins and retromer enable efficient L2-dependent transport of vDNA to the Golgi. Our recent work reveals that this membrane protruding L2/vDNA complex remains at the Golgi until the onset of mitosis, when the Golgi naturally disperses coincident with chromosome condensation, centriole migration, spindle assembly, and nuclear envelope breakdown. During this brief period of dynamic changes, the vesicle-bound membrane-protruding L2/lumenal vDNA complex egresses from the vesiculating Golgi, localizes near centrosomes by prometaphase, and appears to traverse along the spindle, reaching the condensed chromosomes by metaphase. At this time, we believe L2 uses a chromatin- binding domain to physically tether to host chromosomes, a function that is essential for full translocation of the vDNA out of the post-Golgi vesicle. This chromosome-tethered L2/vDNA then partitions into daughter cells to establish a persistent infection of basal keratinocytes. Herein, we propose studies aimed at understanding the fascinating biological mechanisms and implications of L2 subcellular trafficking and mitosis-dependent translocation. Specifically, we aim to understand the nature of the membrane-protruding L2/vDNA complex and the role of furin in achieving this conformation, as well as determine the timing and locale of mitosis- dependent translocation of L2/vDNA from post-Golgi vesicle to metaphase chromosome. Finally, we will explore the biological consequences of this unique trafficking and translocation with regards to innate immune surveillance. These fundamental processes likely contribute towards viral evasion of early innate immune responses and may influence the establishment of persistent infections- hallmarks of oncogenic HPVs that undoubtedly contributes to the oncogenic nature of these viruses.
Terms: <Address><Adopted><Anogenital cancer><Antiviral Agents><Antiviral Drugs><Antivirals><Bacterial Toxins><Binding><Biological><Biology><Body Tissues><Cancers><Capsid><Capsid Protein L2><Capsid protein L1><Causality><Cell Body><Cell Growth in Number><Cell Multiplication><Cell Nucleus><Cell Proliferation><Cell surface><Cells><Cellular Membrane><Cellular Proliferation><Cellular biology><Centrioles><Centrosome><Cervical Cancer><Cervix Cancer><Chromatin><Chromosome Condensation><Chromosomes><Complex><Cutaneous><Cytosol><DNA><DNA Viruses><Data><Deoxyribonucleic Acid><Detection><Double Stranded DNA Virus><Double-Stranded DNA><Elements><Ensure><Epithelial><Esteroproteases><Etiology><Event><Family><Foundations><Future><Genetic Materials><Genome><Goals><Golgi><Golgi Apparatus><Golgi Complex><HPV><HPV 16><HPV L1 oncogene viral capsid protein><HPV L1 protein><HPV L2><HPV L2 oncogene viral capsid protein><HPV infection><HPV-16><HPV16><Human Papilloma Virus><Human Papillomavirus><Human papilloma virus HPV L1 protein><Human papilloma virus L1 protein><Human papilloma virus infection><Human papilloma virus type 16><Human papillomavirus 16><Human papillomavirus HPV L1 protein><Human papillomavirus L1 protein><Human papillomavirus infection><Human papillomavirus type 16><Hydrophobicity><IFN><Immune><Immune Surveillance><Immunes><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunosurveillance><Infection><Infectious Human Wart Virus><Innate Immune Response><Interferons><Interphase><Knowledge><L1 viral capsid protein><L2 viral capsid protein><Life Cycle><Life Cycle Stages><Locales><M Phase><Malignant Cervical Neoplasm><Malignant Cervical Tumor><Malignant Nasopharyngeal Neoplasm><Malignant Nasopharyngeal Tumor><Malignant Neoplasm of the Cervix><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Cervix><Malignant Tumor of the Cervix Uteri><Malignant Tumor of the Nasopharynx><Malignant Uterine Cervix Neoplasm><Malignant Uterine Cervix Tumor><Malignant neoplasm of cervix uteri><Malignant neoplasm of nasopharynx><Mediating><Membrane><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Metaphase><Micro-tubule><Microtubules><Minor><Mitosis><Mitosis Stage><Mitotic><Mitotic Chromosome><Mitotic Metaphase><Modeling><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Mucosa><Mucosal Tissue><Mucous Membrane><N-terminal><NH2-terminal><Nasopharyngeal Cancer><Nasopharynx Cancer><Nature><Nuclear Envelope><Nuclear Membrane><Nucleus><Oncogenic><Pathway interactions><Penetration><Peptidases><Peptide Hydrolases><Pro-Metaphase><Process><Prometaphase><Protease Gene><Proteases><Protein Cleavage><Proteinases><Proteolysis><Proteolytic Enzymes><Role><Sensory><Sexually Transmitted Diseases><Sexually Transmitted Disorder><Sexually Transmitted Infection><Site><Sorting - Cell Movement><Stimulator of Interferon Genes><Structure><Surface Proteins><System><TM Domain><Time><Tissues><Transmembrane Domain><Transmembrane Region><United States><Uterine Cervix Cancer><Vaccination><Venereal Diseases><Venereal Disorders><Venereal Infections><Vesicle><Viral><Virion><Virus><Virus Particle><Woman><Work><anti-viral agents><anti-viral drugs><anti-virals><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><causation><cell biology><chronic infection><conformation><conformational state><daughter cell><dimer><disease causation><ds-DNA><dsDNA><dsDNA Virus><fascinate><high risk><human papilloma virus 16><human papilloma virus L2><human papillomavirus L2><innate immune pathways><innovate><innovation><innovative><insight><keratinocyte><keratinocyte differentiation><life course><malignancy><membrane activity><membrane structure><men><men's><migration><neoplasm/cancer><novel><pathogen><pathway><persistent infection><recruit><residence><residential building><residential site><response><sensory system><social role><sorting><sorting nexins><trafficking><trans-Golgi Network><type 16 Human papilloma virus><type 16 Human papillomavirus><wart virus>