1. Oxana A. Malakhova1,3,
2. Ming Yan1,3,
3. Michael P. Malakhov1,
4. Youzhong Yuan1,
5. Kenneth J. Ritchie1,
6. Keun Il Kim1,
7. Luke F. Peterson1,
8. Ke Shuai2, and
9. Dong-Er Zhang1,4

1. ¹Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA;²Division of Hematology/Oncology, University of California at Los Angeles, School of Medicine, Los Angeles, California 90095, USA

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.

Keywords

• ISG15
• UBP43
• knockout
• interferon
• STAT
• JAK

Footnotes

• ↵3 These authors contributed equally to this work.

• ↵4 Corresponding author.

• E-MAILdzhang{at}scripps.edu; FAX (858) 784-9593.

• Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1056303.

• • Received November 4, 2002.
  • Accepted December 24, 2002.
• Cold Spring Harbor Laboratory Press

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