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PMID: 12600939 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Protein ISGylation modulates the JAK-STAT signaling pathway.

Genes & development ·Vol. 17 ·No. 4 ·2003-02-15 ·Pages 455-60

Malakhova OA, Yan M, Malakhov MP, Yuan Y, Ritchie KJ, Kim KI, Peterson LF, Shuai K, Zhang DE

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.

MeSH Terms
Animals Apoptosis/drug effects Bone Marrow Transplantation Cytokines/drug effects,metabolism DNA-Binding Proteins/metabolism Endopeptidases/genetics,metabolism Hematopoietic Stem Cells/drug effects Humans Interferon Inducers/pharmacology Interferon-beta/metabolism,pharmacology Janus Kinase 1 K562 Cells/drug effects Ligases/genetics,metabolism Mice Mice, Inbred C57BL Mice, Mutant Strains Phosphorylation Poly I-C/pharmacology Promoter Regions, Genetic Protein-Tyrosine Kinases/drug effects,metabolism STAT1 Transcription Factor Signal Transduction Trans-Activators/metabolism Tyrosine Ubiquitin Thiolesterase Ubiquitin-Protein Ligases Ubiquitins/analogs & derivatives
Chemicals
Cytokines DNA-Binding Proteins G1p2 protein, mouse Interferon Inducers STAT1 Transcription Factor STAT1 protein, human Stat1 protein, mouse Trans-Activators Ubiquitins Tyrosine ISG15 protein, human Interferon-beta Ubiquitin-Protein Ligases Protein-Tyrosine Kinases JAK1 protein, human Jak1 protein, mouse Janus Kinase 1 Endopeptidases Usp18 protein, mouse USP18 protein, human Ubiquitin Thiolesterase Ligases Poly I-C
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Malakhova Oxana A
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
Yan Ming
Malakhov Michael P
Yuan Youzhong
Ritchie Kenneth J
Kim Keun Il
Peterson Luke F
Shuai Ke
Zhang Dong-Er
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1056303
Published
2003-02-15
Pages
455-60
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC195994
Subset
IM
External Links
PubMed source DOI: 10.1101/gad.1056303 PMC Full Text View journal details
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