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

Nature Medicine volume 10, pages 1374–1378 (2004)Cite this article

Abstract

Innate immune responses provide the host with an early protection barrier against infectious agents, including viruses, and help shape the nature and quality of the subsequent adaptive immune responses of the host1. Expression of ISG15 (UCRP), a ubiquitin-like protein, and protein ISGylation are highly increased upon viral infection2,3,4. We have identified UBP43 (USP18) as an ISG15 deconjugating protease5. Protein ISGylation is enhanced in cells deficient in UBP43 (ref. 6). Here we have examined the role of UBP43, encoded by the gene Usp18, in innate immunity to virus infection. Usp18−/− mice were resistant to the fatal lymphocytic choriomeningitis and myeloencephalitis that developed in wild-type mice after intracerebral inoculation with lymphocytic choriomeningitis virus (LCMV) or vesicular stomatitis virus (VSV), respectively. Survival of Usp18−/− mice after intracerebral LCMV infection correlated with a severe inhibition of LCMV RNA replication and antigen expression in the brain and increased levels of protein ISGylation. Consistent with these findings, mouse embryonic fibroblasts (MEF) and bone marrow–derived macrophages from Usp18−/− mice showed restricted LCMV replication. Moreover, MEF from Usp18−/− mice showed enhanced interferon-mediated resistance to the cytopathic effect caused by VSV and Sindbis virus (SNV). This report provides the first direct evidence that the ISG15 protease UBP43 and possibly protein ISGylation have a role in innate immunity against viral infection.

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Figure 1: LCMV infection induces expression of ISG15 in brain and immunohistochemical analysis of meninges of wild-type and Usp18−/− mice.
Figure 2: Protection from lethal LCMV and VSV infection in Usp18−/− mice.
Figure 3: Diminished virus-specific T-cell responses to LCMV in Usp18−/− mice and impaired replication of LCMV in Usp18−/− cells.
Figure 4: Usp18-deficient cells are more resistant to viral infection and normal levels of LCMV multiplication are restored in Usp18+/−Ifnar1−/− mice.

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Acknowledgements

We thank members of the DEZ laboratory for valuable discussions, M. Shen and J. Kuan for animal husbandry and genotyping, K. Edelmann for assistance with the analysis of virus-specific T-cell responses. This work is supported by National Institutes of Health Grants CA079849 (DEZ), GM066955 (DEZ), and AI047140 (JCT). The Stein Endowment Fund has partially supported the Department of Molecular and Experimental Medicine departmental molecular biology service laboratory for DNA sequencing and oligonucleotide synthesis. This is manuscript 16008-MEM from The Scripps Research Institute.

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Authors and Affiliations

  1. Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, 92037, California, USA

    Kenneth J Ritchie, Keun Il Kim, Ming Yan & Dong-Er Zhang

  2. Immunology Platform, Aventis Pharmaceuticals, Bridgewater, 08807, New Jersey, USA

    Chang S Hahn & Li Li

  3. Department of Neuropharmacology, The Scripps Research Institute, La Jolla, 92037, California, USA

    Dabralee Rosario & Juan Carlos de la Torre

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  1. Kenneth J Ritchie
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Correspondence to Juan Carlos de la Torre or Dong-Er Zhang.

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Ritchie, K., Hahn, C., Kim, K. et al. Role of ISG15 protease UBP43 (USP18) in innate immunity to viral infection. Nat Med 10, 1374–1378 (2004). https://doi.org/10.1038/nm1133

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