Protein ISGylation modulates the JAK-STAT signaling pathway.
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.
Malakhova
Oxana A
OA
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
Yan
Ming
M
Malakhov
Michael P
MP
Yuan
Youzhong
Y
Ritchie
Kenneth J
KJ
Kim
Keun Il
KI
Peterson
Luke F
LF
Shuai
Ke
K
Zhang
Dong-Er
DE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016026:Bone Marrow Transplantation; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology; D016899:Interferon-beta / Q000378:metabolism / Q000494:pharmacology; D053613:Janus Kinase 1; D020014:K562 Cells / Q000187:drug effects; D008025:Ligases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010766:Phosphorylation; D011070:Poly I-C / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014443:Tyrosine; D043222:Ubiquitin Thiolesterase; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000031:analogs & derivatives*
D016207:Cytokines; D004268:DNA-Binding Proteins; C489550:G1p2 protein, mouse; D007369:Interferon Inducers; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014452:Ubiquitins; D014443:Tyrosine; C074034:ISG15 protein, human; D016899:Interferon-beta; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D010450:Endopeptidases; C118306:Usp18 protein, mouse; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase; D008025:Ligases; D011070:Poly I-C