Protein ISGylation modulates the JAK-STAT signaling pathway
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-β 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.
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Footnotes
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↵3 These authors contributed equally to this work.
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↵4 Corresponding author.
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E-MAIL dzhang{at}scripps.edu; FAX (858) 784-9593.
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Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1056303.
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- Received November 4, 2002.
- Accepted December 24, 2002.
- Cold Spring Harbor Laboratory Press