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Title: The Role of the Pyrin Domain in the Antiviral Functions of DNA Sensor Interferon-Inducible Protein 16
Authors: Pan, Catherina
Advisors: Cristea, Ileana M
Department: Molecular Biology
Certificate Program: Global Health and Health Policy Program
Class Year: 2018
Abstract: Herpes simplex viruses (HSV) cause some of the most contagious sexually transmitted infections (STI) in the world. Investigation into human intrinsic and innate immune defense is therefore essential to the development of prophylactic vaccines. Recently, a human nuclear DNA sensor interferon-inducible protein 16 (IFI16) was discovered to have antiviral functions against DNA viruses. IFI16 represses transcription of immediate-early (IE) and early viral genes, decreases viral protein levels, and induces cytokine expression. Furthermore, IFI16 function is inhibited by many herpesviruses, such as human cytomegalovirus (HCMV) via sequestration of the IFI16 pyrin domain (PYD). Functionally, IFI16 PYD enables IFI16 oligomerization at the nuclear periphery of the cell at early stage of viral infection. This thesis aims to determine the mechanism of IFI16 oligomerization and its functional importance. Using fluorescence microscopy, we found that loss of charge at IFI16 putative surface residues disrupted nuclear periphery enrichment of IFI16 during viral infections. Western blots, quantitative real-time PCRs, and viral titer assays confirmed that intact PYD oligomerization is crucial for IFI16 repression of viral gene transcription and efficient replication. Through chromatin immunoprecipitation, we observed that heterochromatin markers on viral genes were markedly reduced on PYD oligomerization mutants, supporting the hypothesis that the capacity of IFI16 to homotypically assemble is critical for its role as an immune protein. This study sheds light on the mechanism of function of IFI16 and provides insight into how the protein enables human intrinsic and innate immune defense against herpesviruses.
Type of Material: Princeton University Senior Theses
Language: en
Appears in Collections:Molecular Biology, 1954-2023
Global Health and Health Policy Program, 2017-2023

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