Mice Lacking the ISG15 E1 Enzyme UbE1L Demonstrate Increased Susceptibility to both Mouse-Adapted and Non-Mouse-Adapted Influenza B Virus Infection

Lai, Caroline; Struckhoff, Jessica J.; Schneider, Jana; Martínez-Sobrido, Luis; Wolff, Thorsten; Garcı́a-Sastre, Adolfo; Zhang, Dong‐Er; Lenschow, Deborah J.

doi:10.1128/jvi.00105-08

Cited by 121 publications

(105 citation statements)

References 34 publications

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“…Consistent with this conclusion, ISG15 and Ube1L knockout mice were shown to be more susceptible to influenza B virus replication (15). However, these results raised another issue: Why was the NS1B protein unable to protect influenza B virus from the antiviral effects of ISG15 conjugation in wild-type mice?…”

supporting

confidence: 69%

Structural basis for the sequence-specific recognition of human ISG15 by the NS1 protein of influenza B virus

Guan

Chung

Leonard

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Interferon-induced ISG15 conjugation plays an important antiviral role against several viruses, including influenza viruses. The NS1 protein of influenza B virus (NS1B) specifically binds only human and nonhuman primate ISG15s and inhibits their conjugation. To elucidate the structural basis for the sequence-specific recognition of human ISG15, we determined the crystal structure of the complex formed between human ISG15 and the N-terminal region of NS1B (NS1B-NTR). The NS1B-NTR homodimer interacts with two ISG15 molecules in the crystal and also in solution. The two ISG15-binding sites on the NS1B-NTR dimer are composed of residues from both chains, namely residues in the RNA-binding domain (RBD) from one chain, and residues in the linker between the RBD and the effector domain from the other chain. The primary contact region of NS1B-NTR on ISG15 is composed of residues at the junction of the N-terminal ubiquitin-like (Ubl) domain and the short linker region between the two Ubl domains, explaining why the sequence of the short linker in human and nonhuman primate ISG15s is essential for the species-specific binding of these ISG15s. In addition, the crystal structure identifies NS1B-NTR binding sites in the N-terminal Ubl domain of ISG15, and shows that there are essentially no contacts with the C-terminal Ubl domain of ISG15. Consequently, NS1B-NTR binding to ISG15 would not occlude access of the C-terminal Ubl domain of ISG15 to its conjugating enzymes. Nonetheless, transfection assays show that NS1B-NTR binding of ISG15 is responsible for the inhibition of interferoninduced ISG15 conjugation in cells.

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supporting

confidence: 69%

Structural basis for the sequence-specific recognition of human ISG15 by the NS1 protein of influenza B virus

Guan

Chung

Leonard

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…ISG15 exists in three forms: (i) a free, unconjugated intracellular protein, (ii) conjugated to viral and/or host target proteins, and (iii) an extracellular cytokine (Recht et al, 1991;D'Cunha et al, 1996a, b;Lai et al, 2009). All three forms could potentially affect HCV viral production.…”

Section: Discussionmentioning

confidence: 99%

ISG15, a ubiquitin-like interferon-stimulated gene, promotes hepatitis C virus production in vitro: implications for chronic infection and response to treatment

Chen

Sun

Meng

et al. 2009

Journal of General Virology

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Upregulation of interferon (IFN)-stimulated genes (ISGs), including IFN-stimulated gene 15 (ISG15) and other members of the ISG15 pathway, in pre-treatment liver tissue of patients chronically infected with hepatitis C virus (HCV) is associated with subsequent treatment failure (pegylated IFN-a/ribavirin). This study assessed the effect of ISG15 on HCV production in vitro. The levels of ISG15 and of its conjugation to target proteins (ISGylation) were increased by plasmid transfection, but ISGylation was inhibited by small interfering RNA directed against the E1 activating enzyme, Ube1L, in Huh7.5 cells. Cells were infected with HCV FL-J6/JFH virus, and HCV RNA and viral titres were determined. Levels of both HCV RNA and virus increased when levels of ISG15 and ISGylation were increased, and decreased when ISGylation was inhibited. The effects of ISGylation on HCV were independent of upstream IFN signalling: IFN-a-induced ISG expression was not altered by Ube1L knockdown. Thus, although ISG15 has antiviral activity against most viruses, ISG15 promotes HCV production. HCV might exploit ISG15 as a host immune evasion mechanism, and this may in part explain how increased expression of ISGs, especially ISG15, correlates with subsequent IFN-based treatment failure. INTRODUCTIONHepatitis C virus (HCV) is adept at evading host antiviral mechanisms and is often resistant to the current standard of care -combination treatment with pegylated interferon (IFN)-a and ribavirin (PegIFN/Rib). This regimen eradicates the virus in only 50 % of cases. A number of mechanisms contribute to evasion and treatment resistance, including cleavage of the RIG-I adaptor protein IPS1/ MAVS/Cardif by the HCV NS3/NS4A protease and modulation of the host response by the HCV core protein Loo et al., 2006). However, none of these mechanisms has consistently been demonstrated to play a role in the clinical disease and thus cannot explain the ability of the virus to escape the host response in patients.Response to treatment can be predicted by levels of expression of IFN-stimulated genes (ISGs) in the liver prior to initiation of PegIFN/Rib treatment. Non-responders have increased expression of a number of ISGs (Chen et al., 2005;Feld et al., 2007; Asahina et al., 2008;Asselah et al., 2008;Sarasin-Filipowicz, et al., 2008). Three of these ISGs are components of the ISG15 ubiquitin-like pathway. ISG15 was the first ubiquitin-like protein to be described and, like its homologue ubiquitin, is conjugated to proteins in a tightly regulated process called ISGylation. The ISG15 E1 activating protein, Ube1L, coordinates with the E2 conjugating enzyme (UbcH8) and the E3 ligase (CEB1) to join the C terminus of ISG15 to a wide variety of proteins (Loeb & Haas, 1992). ISG15 can be removed from its target proteins by USP18, an ISG15 protease (Kim et al., 2008b). Thus, ISG15 inhibits virus production for many viruses, but may promote production of some.In this study, we examined the role of ISG15 and ISGylation in HCV production in vitro, using the FL-J6/JFH...

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“…Interestingly, the increased lethality of IFN-a/bR 2/2 and ISG15 2/2 mice upon Sindbis virus infection can only be rescued by a recombinant virus expressing wild-type (WT) ISG15, but not ISG15 (AA) mutant, which cannot form conjugates (41,42). Mice lacking Ube1L, the ISG15 E1 enzyme, show increased susceptibility to both Sindbis virus and influenza B virus infection (46,47). In addition, influenza B virus NS1 binds ISG15 at its N terminus and blocks cellular ISGylation (25).…”

Section: And Isg15mentioning

confidence: 99%

Herc5 Attenuates Influenza A Virus by Catalyzing ISGylation of Viral NS1 Protein

Tang

Zhong

Zhu

et al. 2010

The Journal of Immunology

133

136

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Ubiquitin-like protein ISG15, which is robustly induced by IFN or virus, is implicated to inhibit influenza A virus (IAV) in vivo. But the underlying mechanism still remains largely unknown. In this study, we report that Herc5 could catalyze conjugation of ISG15 onto IAV-NS1 protein, the critical virulence factor of IAV. This modification produces two more species, respectively mapped to IAV-NS1 at lysine 20, 41, 217, 219, and 108, 110, and 126. The ISGylated IAV-NS1 fails to form homodimers and inhibits relevant antiviral processes. Knockdown of Herc5 or ISG15 could partially alleviate IFN-β–induced antiviral activities against IAV, whereas ectopic expression of the Herc5-mediated ISGylation system could distinctly potentiate IFN-β–induced antiviral effects against IAV. Notably, IAV-NS1s of H5N1 avian IAVs display less ISGylation species than that of IAV-PR8/34 (human H1N1). Consistently, IAV-PR8/34 mutants deprived of IAV-NS1’s ISGylation exhibit augmented viral propagation and virulence in both cultured cells and mice. Our study reports the first microbial target of ISGylation and uncovers the direct antiviral function and mechanism of this novel modification.

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Mice Lacking the ISG15 E1 Enzyme UbE1L Demonstrate Increased Susceptibility to both Mouse-Adapted and Non-Mouse-Adapted Influenza B Virus Infection

Cited by 121 publications

References 34 publications

Structural basis for the sequence-specific recognition of human ISG15 by the NS1 protein of influenza B virus

Structural basis for the sequence-specific recognition of human ISG15 by the NS1 protein of influenza B virus

ISG15, a ubiquitin-like interferon-stimulated gene, promotes hepatitis C virus production in vitro: implications for chronic infection and response to treatment

Herc5 Attenuates Influenza A Virus by Catalyzing ISGylation of Viral NS1 Protein

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