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Principal Investigator: Stephen A DiGiuseppe
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2019
Award: $53,150
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
Poxviruses are a family of DNA viruses that have afflicted humans throughout
history. Notably, smallpox devastated the human population by killing more people than
any other disease. Despite being eradicated, the threat of emerging poxviruses is still a
reality. New human poxviruses are still being discovered and evolving zoonotic
infections like African monkeypox have experts concerned it is only matter of time
before a new smallpox-like disease emerges. In fact, there is an ongoing monkeypox
outbreak in Nigeria as of September 2017. Although live smallpox vaccines can protect
against other poxviruses, they are too dangerous for pregnant women, those with
eczema, and the immunocompromised, leaving large portions of the population
unprotected. Poxviruses are also used as oncolytics and gene therapy vectors, while in
basic research they been invaluable tools that uncovered important biological processes
such as mRNA capping and polyadenylation. Therefore, research into poxviruses
continues to be significant for both clinical and basic research.
Poxviruses are incredibly self-sufficient and encode almost everything they need
to replicate. Despite this, poxviruses still rely on host ribosomes to translate viral
mRNAs and have evolved strategies to hijack them. Recent evidence suggests that
ribosomes have the capacity to be ‘specialized’ to selectively translate mRNAs. What
dictates this ‘specialization’ is largely unknown, but evidence suggests that changes to
the subunit composition and/or post-translational modifications (PTMs) to ribosomal
subunit proteins plays a key role. It was recently uncovered that following activation of
ribosome quality control (RQC), two factors, ZNF598 and RACK1, induce PTMs on the
ribosomal complex. Our lab recently discovered that poxviruses uniquely modify RACK1
to selectively enhance translation of viral mRNAs. Curiously, preliminary data shows
ZNF598 is also required for infection suggesting a link between RQC pathways and
infection. Therefore, we hypothesize poxviruses usurp RQC factors by inducing
PTMs to ‘specialize’ the ribosome to selectively enhance translation of viral
mRNAs. We devised two specific aims that focus on determining what roles ZNF598
and RACK1 play during infection. Knowledge gained would not only further our
understanding of poxvirus biology, but would also provide valuable insights into the
RQC pathway and identify novel therapeutic targets to treat poxvirus-related diseases.
Terms: <0-11 years old><Affect><African><Basic Research><Basic Science><Biological Function><Biological Process><Biology><Cancer Treatment><Cell Body><Cells><Child><Child Youth><Children (0-21)><Clinic><Clinical Research><Clinical Study><Co-Immunoprecipitations><Complex><Cytoplasm><DNA Viruses><Dangerousness><Data><Defect><Disease><Disease Outbreaks><Disorder><E3 Ligase><E3 Ubiquitin Ligase><Eczema><Eczematous Dermatitis><Family><Future><Gene Therapy Vectors><Gene Transduction Agent><Gene Transduction Vectors><General Viruses><Genetic Alteration><Genetic Change><Genetic defect><Genome><Goals><History><Host Factor><Host Factor Protein><Human><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><Infection><Integration Host Factors><Kinases><Knock-out><Knockout><Knowledge><Link><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Measures><Messenger RNA><Modern Man><Modification><Molecular><Monkey Pox><Monkeypox><Mutation><Nature><Nigeria><Oncolytic><Outbreaks><Pathway interactions><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Play><Poly(A)+ mRNA><Polyadenylated mRNA><Polyadenylation Pathway><Population><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Poxviridae><Poxviridae Infections><Poxviridae disease><Poxvirus Infections><Poxvirus officinale><Poxviruses><Pregnant Women><Production><Protein Biosynthesis><Protein Modification><Protein Phosphorylation><Protein Subunits><Proteins><Quality Control><RNA Viruses><Recording of previous events><Reporter><Research><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Ribosomal Proteins><Ribosomes><Role><Site><Skin><Smallpox><Smallpox Vaccine><Specificity><Testing><Therapeutic><Time><Translating><Translations><Transphosphorylases><Ubiquitilation><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Ubiquitination><Ubiquitinoylation><Vaccinia virus><Variola><Viral><Viral Diseases><Virus><Virus Diseases><Work><Zoonoses><Zoonotic><Zoonotic Infection><anti-cancer therapy><anticancer therapy><cancer therapy><children><childrens'><eczematous><expectant mother><expecting mother><genome mutation><immunosuppressed patient><insight><mRNA><mRNA capping><mRNA polyadenylation><mutant><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pathway><polyadenylated messenger RNA><pox virus><pregnant mothers><protein synthesis><recombinant vaccinia virus><sensor><small pox><small pox vaccine><social role><tool><ubiquination><ubiquitin conjugation><ubiquitin-protein ligase><variola major><viral infection><virus host interaction><virus infection><virus-induced disease><youngster>