Enhanced antibacterial potential in UBP43-deficient mice against Salmonella typhimurium infection by up-regulating type I IFN signaling.
ISG15 is an IFN-inducible ubiquitin-like protein and its expression and conjugation to target proteins are dramatically induced upon viral or bacterial infection. We have generated a UBP43 knockout mouse model that is lacking an ISG15-specific isopeptidase to study the biological role of the protein ISGylation system. We report that UBP43-deficient mice are hypersensitive to LPS-induced lethality and that TIR domain-containing adapter inducing IFN-beta --> IFN regulatory factor 3 --> type I IFN is the major axis to induce protein ISGylation and UBP43 expression in macrophages upon LPS treatment. In ubp43(-/-) macrophages, upon LPS treatment we detected increased expression of IFN-stimulated genes, including genes for several cytokines and chemokines involved in the innate immune response. The ubp43(-/-) mice were able to restrict the growth of Salmonella typhimurium more efficiently than wild-type mice. These results clearly demonstrate two aspects of IFN-signaling, a beneficial effect against pathogens but a detriment to the body without strict control.
Departments of Molecular and Experimental Medicine and Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Keun Il
KI
Kim
Oxana A
OA
Malakhova
Kasper
K
Hoebe
Ming
M
Yan
Bruce
B
Beutler
Dong-Er
DE
Zhang
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000502:physiology; D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D010450:Endopeptidases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D007370:Interferon Type I / Q000502:physiology*; D053613:Janus Kinase 1; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011971:Receptors, Immunologic / Q000378:metabolism; D012481:Salmonella Infections, Animal / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control*; D012486:Salmonella typhimurium / Q000254:growth & development / Q000276:immunology*; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology / Q000401:mortality; D051197:Toll-Like Receptor 4; D043222:Ubiquitin Thiolesterase; D014452:Ubiquitins / Q000096:biosynthesis / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D010450:Endopeptidases; D007370:Interferon Type I; D053613:Janus Kinase 1; D008024:Ligands; D008070:Lipopolysaccharides; D011505:Protein-Tyrosine Kinases; D011971:Receptors, Immunologic; D051197:Toll-Like Receptor 4; D043222:Ubiquitin Thiolesterase; D014452:Ubiquitins; C489550:G1p2 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse; C507905:Jak1 protein, mouse; C118306:Usp18 protein, mouse