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Principal Investigator: Ram Savan
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2024
Award: $632,371
Funding agency: National Institute of Allergy and Infectious Diseases
Summary
In this proposal, we will explore the role of prenylation in antiviral immunity. Prenylation is a post-translational
modification that renders proteins hydrophobic, thus targeting them to the endomembrane. While the role of
prenylation in immunity is unclear, our preliminary data shows compelling evidence that prenylation is a
modification widely used in innate antiviral immunity. As both the host and virus utilize prenylation and the
cholesterol biosynthetic pathway, we propose a dynamic host-pathogen interaction at this interface. We
hypothesize that prenylation could be a potent host innovation to counter viral pathogenesis. This is based on
in silica analysis that revealed an enrichment of immunity-related proteins with a prenylation motif. We
followed in-silica analyses with a biochemical screen and identified several prenylated antiviral proteins that
are involved in interferon responses and virus restriction, with potential to affect virus entry, replication, and
egress. In this grant, we propose to identify the functional consequences of prenylated proteins on subcellular
localization, interferon signaling, and antiviral function. By perturbing specific enzymes in the prenylation
pathway, we will study its effect on interferon response, antiviral effectors, and virus control. This work will
provide novel insights into cell-intrinsic antiviral countermeasures and the development of novel antiviral drug
targets.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ADP-Ribosylation Factor GTPase-Activating Protein with FG Repeats 1><AGFG1><AGFG1 gene><ARFGAP with FG Repeats 1><Affect><Alpha Virus><Anti-viral Agents><Anti-viral Response><Biochemical><Biological Markers><Blood monocyte><C-terminal><COVID-19 virus><COVID19 virus><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chemicals><Cholesterol><Clinic><CoV-2><CoV2><Coronaviridae><Coronavirus><Cristobalite><DNA><Data><Deoxyribonucleic Acid><Development><Drug Targeting><Egypt 101 virus><Enterovirus><Enzyme Gene><Enzymes><Family><Family Picornaviridae><Flavivirus><Genes><Grant><Group A Arboviruses><Group B Arbovirus><HIV-1 REV-Binding Protein><HRB gene><HRB protein><Host Defense><Hydrophobicity><IFN><Immune><Immune response><Immune system><Immunes><Immunity><Immunological response><Infection><Innate Immunity><Interferons><Intracellular Communication and Signaling><Life Cycle><Life Cycle Stages><Ligase><Ligase Gene><Lipids><Location><Malignant Neoplasms><Malignant Tumor><Marrow monocyte><Membrane><Modification><Native Immunity><Natural Immunity><Non-Polyadenylated RNA><Non-Specific Immunity><Nonspecific Immunity><Orthoflavivirus><Pathway interactions><Phase><Picornaviridae><Picornaviruses><Play><Population><Post-Translational Isoprenylation><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Isoprenylation><Posttranslational Modifications><Posttranslational Protein Processing><Predisposition><Protein Isoprenylation><Protein Modification><Protein Prenylation><Proteins><Proteome><RAB gene><RAB protein><REV-Interacting Protein><REV/REX Activation Domain-Binding Protein><RIP gene><RIP protein><RNA><RNA Gene Products><RNA Viruses><Ribonucleic Acid><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sand><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Silica><Silicon Dioxide><Site><Specificity><Susceptibility><Synthetases><Tail><Testing><Therapeutic Effect><Tridymite><Viral><Viral Activity><Viral Diseases><Viral Function><Viral Gene Products><Viral Gene Proteins><Viral Pathogenesis><Viral Physiology><Viral Proteins><Virus><Virus Diseases><Virus Replication><WNV><West Nile virus><Work><Wuhan coronavirus><ZIKV><Zika Virus><Zinc Finger Domain><Zinc Finger Motifs><Zinc Fingers><anti-viral compound><anti-viral drugs><anti-viral immunity><anti-viral medication><anti-viral therapeutic><anti-virals><antiviral immunity><bio-markers><biologic marker><biological signal transduction><biomarker><corona virus><coronavirus disease 2019 virus><coronavirus disease-19 virus><developmental><hCoV19><host response><immune system response><immunoresponse><inhibitor><innovate><innovation><innovative><insight><life course><malignancy><membrane structure><monocyte><nCoV2><neoplasm/cancer><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><oligoadenylate><pathogen><pathogenic virus><pathway><prenylation><programs><response><social role><viral infection><viral multiplication><viral pathogen><viral replication><virus infection><virus multiplication><virus pathogen><virus pathogenesis><virus protein><virus-induced disease><zikav>