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USP18 - a multifunctional component in the interferon response.

ABSTRACT: Ubiquitin-specific proteases (USPs) represent the largest family of deubiquitinating enzymes (DUB). These proteases cleave the isopeptide bond between ubiquitin and a lysine residue of a ubiquitin-modified protein. USP18 is a special member of the USP family as it only deconjugates the ubiquitin-like protein ISG15 (interferon-stimulated gene (ISG) 15) from target proteins but is not active towards ubiquitin. Independent of its protease activity, USP18 functions as a major negative regulator of the type I interferon response showing that USP18 is - at least - a bifunctional protein. In this review, we summarise our current knowledge of protease-dependent and -independent functions of USP18 and discuss the structural basis of its dual activity.

SUBMITTER: Basters A

PROVIDER: S-EPMC6240716 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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USP18 - a multifunctional component in the interferon response.

Basters Anja A Knobeloch Klaus-Peter KP Fritz Günter G

Bioscience reports 20181115 6

Ubiquitin-specific proteases (USPs) represent the largest family of deubiquitinating enzymes (DUB). These proteases cleave the isopeptide bond between ubiquitin and a lysine residue of a ubiquitin-modified protein. USP18 is a special member of the USP family as it only deconjugates the ubiquitin-like protein ISG15 (interferon-stimulated gene (ISG) 15) from target proteins but is not active towards ubiquitin. Independent of its protease activity, USP18 functions as a major negative regulator of t ...[more]

PMID: 30126853

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Project description:HIV-1 infection persists in humans despite expression of antiviral type 1 interferons (IFN). Even exogenous administration of IFNα only marginally reduces HIV-1 abundance, raising the hypothesis that people living with HIV-1 (PLWH) are refractory to type 1 IFN. We demonstrated type 1 IFN refractoriness in CD4+ and CD8+ T cells isolated from HIV-1 infected persons by detecting diminished STAT1 phosphorylation (pSTAT1) and interferon-stimulated gene (ISG) induction upon type 1 IFN stimulation compared to healthy controls. Importantly, HIV-1 infected people who were virologically suppressed with antiretrovirals also showed type 1 IFN refractoriness. We found that USP18 levels were elevated in people with refractory pSTAT1 and ISG induction and confirmed this finding ex vivo in CD4+ T cells from another cohort of HIV-HCV coinfected persons who received exogenous pegylated interferon-α2b in a clinical trial. We used a cell culture model to recapitulate type 1 IFN refractoriness in uninfected CD4+ T cells that were conditioned with media from HIV-1 inoculated PBMCs, inhibiting de novo infection with antiretroviral agents. In this model, RNA interference against USP18 partly restored type 1 IFN responses in CD4+ T cells. We found evidence of type 1 IFN refractoriness in PLWH irrespective of virologic suppression that was associated with upregulated USP18, a process that might be therapeutically targeted to improve endogenous control of infection.ImportancePeople living with HIV-1 (PLWH) have elevated constitutive expression of type 1 interferons (IFN). However, it is unclear whether this impacts downstream innate immune responses. We identified refractory responses to type 1 IFN stimulation in T cells from PLWH, independent of antiretroviral treatment. Type 1 IFN refractoriness was linked to elevated USP18 levels in the same cells. Moreover, we found that USP18 levels predicted the anti-HIV-1 effect of type 1 IFN-based therapy on PLWH. In vitro, we demonstrated that refractory type 1 IFN responses were transferrable to HIV-1 uninfected target CD4+ T cells, and this phenomenon was mediated by type 1 IFN from HIV-1 infected cells. Type 1 IFN responses were partially restored by USP18 knockdown. Our findings illuminate a new mechanism by which HIV-1 contributes to innate immune dysfunction in PLWH, through the continuous production of type 1 IFN that induces a refractory state of responsiveness.

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USP18 - a multifunctional component in the interferon response.

Publications

USP18 - a multifunctional component in the interferon response.

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