Role of ISG15 protease UBP43 (USP18) in innate immunity to viral infection

Ritchie, Kenneth J.; Hahn, Chang S.; Kim, Keun Il; Yan, Ming; Rosario, Dabralee; Li, Li; Torre, Juan Carlos de la; Zhang, Dong‐Er

doi:10.1038/nm1133

Cited by 251 publications

(222 citation statements)

References 29 publications

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“…The importance of USP18 in innate immunity to viral infection was demonstrated using USP18-deficient mice, which were resistant to lymphocytic choriomeningitis virus or vesicular stomatitis virus . 62 Although the exact antiviral activity of the ISG15 pathway remains to be determined, its induction by IKK⑀ may play an important role in the antiviral action of IKK⑀ against HCV.…”

Section: Discussionmentioning

confidence: 99%

The protein kinase IKKε can inhibit HCV expression independently of IFN and its own expression is downregulated in HCV-infected livers

et al. 2006

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H epatitis C virus (HCV) infection leads to the development of chronic hepatitis in 60% to 90% of infected individuals, cirrhosis in 0.5% to 30% of cases, and hepatocellular carcinoma at a rate of 1% to 3% per year. 1 The current approved treatment for HCV infection is pegylated interferon alpha (IFN-␣) in combination with ribavirin. This leads to clearance of the virus in 50% to 80% of cases, depending on the infecting HCV genotype. In particular, HCV of genotype 1 is the most resistant to IFN treatment. 2 HCV can interfere with the response of cells to IFN, through its viral proteins targeting either the IFN-activated JAK/STAT signaling pathway 3-5 or through other processes, leading to inhibition of action of the IFN-induced antiviral proteins. 6 In addition to this, HCV interferes with IFN induction, and more generally, with the induction of the innate immune response. The innate immune response is triggered in response to a variety of pathogens, such as bacteria and viruses, and is essential for a rapid limitation in the spread or action of these pathogens. IFN induction can take place after interaction of extracellular nucleic acids to members of the Toll-like receptor family 7-10 and after viral intrusion in the cytoplasm through the interaction of viral double-stranded RNAs (dsRNAs) with specific RNA helicases, such as RIG-I 11 or MDA-5. 12 For instance, the From the

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Section: Discussionmentioning

confidence: 99%

The protein kinase IKKε can inhibit HCV expression independently of IFN and its own expression is downregulated in HCV-infected livers

et al. 2006

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“…To date, only five cellular targets for protein ISGylation have been reported, including Serpin 2a, Jak1, Stat1, phospholipase C␥1, and Erk1/2 (28,44), among possibly hundreds of ISGylated proteins. We recently report that UBP43-deficient mice are resistant to certain virus infections (45). Currently, it is not clear how protein ISGylation contributes to innate immunity.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Antibacterial Potential in UBP43-Deficient Mice against Salmonella typhimurium Infection by Up-Regulating Type I IFN Signaling

Kim¹,

Malakhova²,

Hoebe

et al. 2005

The Journal of Immunology

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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-β → 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.

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“…Both are important for the control of several viral infections and are crucial mediators of IFNmediated immune responses. 23 GCH1 is the first and rate-limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis. 24 Induction of GCH1 and nitric oxide synthase (NOS) has been suggested to represent two arms of a common pathway required for immunostimulantevoked NO synthesis, and the major function of BH4 may be to support NOS.…”

Section: Transcriptional Host Response During Tularemia H Andersson Ementioning

confidence: 99%

Transcriptional profiling of the peripheral blood response during tularemia

et al. 2006

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Tularemia is a febrile disease caused by the highly contagious bacterium Francisella tularensis. We undertook an analysis of the transcriptional response in peripheral blood during the course of ulceroglandular tularemia by use of Affymetrix microarrays comprising 14 500 genes. Samples were obtained from seven individuals at five occasions during 2 weeks after the first hospital visit and convalescent samples 3 months later. In total, 265 genes were differentially expressed, 95 of which at more than one time point. The differential expression was verified with real-time quantitative polymerase chain reaction for 36 genes (R 2 ¼ 0.590). The most prominent changes were noted in samples drawn on days 2-3 and a considerable proportion of the upregulated genes appeared to represent an interferon-g-induced response and also a proapoptotic response. Genes involved in the generation of innate and acquired immune responses were found to be downregulated, presumably a pathogen-induced event. A logistic regression analysis revealed that seven genes were good predictors of the early phase of tularemia. This is the first description of the transcriptional host response to ulceroglandular tularemia and the study has identified gene subsets relevant to the pathogenesis of the disease and subsets that may serve as early diagnostic biomarkers.

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Role of ISG15 protease UBP43 (USP18) in innate immunity to viral infection

Cited by 251 publications

References 29 publications

The protein kinase IKKε can inhibit HCV expression independently of IFN and its own expression is downregulated in HCV-infected livers

The protein kinase IKKε can inhibit HCV expression independently of IFN and its own expression is downregulated in HCV-infected livers

Enhanced Antibacterial Potential in UBP43-Deficient Mice against Salmonella typhimurium Infection by Up-Regulating Type I IFN Signaling

Transcriptional profiling of the peripheral blood response during tularemia

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