Abstract
ISG15 is one of the most strongly induced genes upon viral infection, type I interferon (IFN) stimulation, and lipopolysaccharide (LPS) stimulation. Here we report that mice lacking UBP43, a protease that removes ISG15 from ISGylated proteins, are hypersensitive to type I IFN. Most importantly, in UBP43-deficient cells, IFN-beta induces a prolonged Stat1 tyrosine phosphorylation, DNA binding, and IFN-mediated gene activation. Furthermore, restoration of ISG15 conjugation in protein ISGylation-defective K562 cells increases IFN-stimulated promoter activity. These findings identify UBP43 as a novel negative regulator of IFN signaling and suggest the involvement of protein ISGylation in the regulation of the JAK-STAT pathway.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Bone Marrow Transplantation
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Cytokines / drug effects
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Cytokines / metabolism*
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DNA-Binding Proteins / metabolism*
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Endopeptidases / genetics*
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Endopeptidases / metabolism
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Hematopoietic Stem Cells / drug effects
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Humans
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Interferon Inducers / pharmacology
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Interferon-beta / metabolism
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Interferon-beta / pharmacology
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Janus Kinase 1
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K562 Cells / drug effects
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Ligases / genetics
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Ligases / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Mutant Strains
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Phosphorylation
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Poly I-C / pharmacology
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Promoter Regions, Genetic
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Protein-Tyrosine Kinases / drug effects
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Protein-Tyrosine Kinases / metabolism*
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STAT1 Transcription Factor
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Signal Transduction
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Trans-Activators / metabolism*
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Tyrosine
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Ubiquitin Thiolesterase
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Ubiquitin-Protein Ligases
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Ubiquitins* / analogs & derivatives*
Substances
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Cytokines
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DNA-Binding Proteins
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G1p2 protein, mouse
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Interferon Inducers
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STAT1 Transcription Factor
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STAT1 protein, human
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Stat1 protein, mouse
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Trans-Activators
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Ubiquitins
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Tyrosine
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ISG15 protein, human
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Interferon-beta
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Ubiquitin-Protein Ligases
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Protein-Tyrosine Kinases
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JAK1 protein, human
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Jak1 protein, mouse
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Janus Kinase 1
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Endopeptidases
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Usp18 protein, mouse
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USP18 protein, human
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Ubiquitin Thiolesterase
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Ligases
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Poly I-C