Document text
Principal Investigator: JON HUIBREGTSE
Organization: UNIVERSITY OF TEXAS AT AUSTIN
Fiscal Year: 2024
Award: $464,326
Funding agency: National Institute of Allergy and Infectious Diseases
SUMMARY
Human ISG15 is a ubiquitin-like protein (Ubl) that functions in innate immune responses, and it is
remarkable for possessing three distinct biochemical activities. As a ubiquitin-like modifier it is conjugated to
hundreds of cellular and viral proteins. The E1, E2, E3, and de-conjugating enzymes for ISG15 (Ube1L/Uba7,
UbcH8/Ube2L6, Herc5, and Usp18, respectively), are, like ISG15, induced at the transcriptional level by Type I
interferon (IFN-α/β) signaling. A second function of ISG15 is as an extracellular signaling protein. ISG15 is
released into the extracellular space from many cell types and signals to Natural Killer and T cells to secrete
IFN-γ, which plays a major role in the response to pathogen infections. The cell surface receptor for
extracellular SG15 is LFA-1, an immune cell-specific integrin. A third function of human ISG15 is that it
negatively regulates Type I IFN signaling, as revealed by the Type I interferonopathy that occurs in some
ISG15-deficient patients; this function of human ISG15 is not shared with mouse ISG15. A challenge in the
field is to understand how the activities of ISG15 are regulated and temporally controlled and which activities
are most closely associated with responses to specific pathogens, including Mycobacterium tuberculosis and
SARS-CoV-2. To further our understanding of ISG15 in innate immune responses to these and other
pathogens, this proposal will focus on the basis of substrate and lysine selectivity of the Herc5/Herc6 family of
ISG15 ligases, the ISG15-induced signaling pathway downstream of LFA-1 that leads to cytokine secretion,
and the mechanism by which ISG15 released into the extracellular space.
Terms: <(IFN) α><(IFN)-α><(IFN)α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><APF-1><ATP-Dependent Proteolysis Factor 1><Alferon><Area><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Binding><Biochemical><Biological><COVID-19 virus><COVID19 virus><CSIF><CSIF-10><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cell Surface Receptors><Cells><Cellular Function><Cellular Physiology><Cellular Process><CoV-2><CoV2><Communicable Diseases><Coronaviridae><Coronavirus><Cytokine Synthesis Inhibitory Factor><Development><Directed Molecular Evolution><Disease><Disorder><Enzyme Gene><Enzymes><Event><Extracellular Space><Family><Gene Transcription><GeneHomolog><Genetic Transcription><Goals><HMG-20><HPGF><Hepatocyte-Stimulating Factor><High Mobility Protein 20><Homolog><Homologous Gene><Homologue><Human><Hybridoma Growth Factor><IFN><IFN Alpha><IFN α><IFN-Gamma><IFN-beta 2><IFN-g><IFN-α><IFN-γ><IFNB2><IFNG><IFNa><IFNα><IFNγ><IL-10><IL-6><IL10><IL10A><IL6 Protein><ISG15><ISG15 gene><Immune><Immune Interferon><Immunes><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Innate Immune Response><Integrins><Integrins Extracellular Matrix><Intercellular Space><Interferon Alfa-n3><Interferon Gamma><Interferon Type I><Interferon Type II><Interferon alpha><Interferon-Induced Protein IFI-15K><Interferon-α><Interferons><Interleukin 10 Precursor><Interleukin-10><Interleukin-6><Intervention><Intervention Strategies><Intracellular Communication and Signaling><L-Lysine><Leukocyte Interferon><Ligase><Ligase Gene><Lymphoblast Interferon><Lymphoblastoid Interferon><Lysine><M tb><M tuberculosis><M. tb><M. tuberculosis><MGI-2><Mediating><Mice><Mice Mammals><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Mycobacterial Infection><Mycobacterium Infections><Mycobacterium tuberculosis><Myeloid Differentiation-Inducing Protein><Patients><Plasmacytoma Growth Factor><Play><Predisposition><Principal Investigator><Process><Proteins><Proteomics><RNA Expression><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><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 Induction><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Site><Structure><Subcellular Process><Susceptibility><Synthetases><T-Cells><T-Lymphocyte><Transcription><Type I Interferonopathy><Ubiquitin><Ubiquitin Like Proteins><Variant><Variation><Vesicle><Viral><Viral Activity><Viral Function><Viral Gene Products><Viral Gene Proteins><Viral Physiology><Viral Proteins><Virus><Wuhan coronavirus><anti-microbial><antimicrobial><beta CoV><beta coronavirus><betaCoV><betacoronavirus><biologic><biological signal transduction><cell type><corona virus><coronavirus disease 2019 virus><coronavirus disease-19 virus><cytokine><developmental><directed evolution><extracellular><gene product><hCoV19><human pathogen><improved><insight><interferon beta 2><interventional strategy><lFN-Gamma><microbe pathogen><microbial><microbial pathogen><mtb><nCoV2><novel><pathogen><pathogenic microbe><pathogenic virus><programs><protein function><response><social role><thymus derived lymphocyte><viral pathogen><virus pathogen><virus protein><β CoV><β coronavirus><βCoV>