ISG15 deficiency and increased viral resistance in humans but not mice

Speer, Scott D.; Li, Zhi; Buta, Sofija; Payelle-Brogard, Béatrice; Li, Qian; Vigant, Frédéric; Rubino, Erminia; Gardner, Thomas J.; Wedeking, Tim; Hermann, Mark; Duehr, James; Sanal, Özden; Tezcan, İlhan; Mansouri, Nahal; Tabarsi, Payam; Mansouri, Davood; François-Newton, Véronique; Daussy, Coralie F.; Rodriguez, Marisela R.; Lenschow, Deborah J.; Freiberg, Alexander N.; Tortorella, Domenico; Piehler, Jacob; Lee, Benhur; Garcı́a-Sastre, Adolfo; Pellegrini, Sandra; Bogunovic, Dusan

doi:10.1038/ncomms11496

Cited by 167 publications

(243 citation statements)

References 59 publications

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“…ISG15 is a complex multi-functional UBL involved in several aspects of innate immune responses to viral and microbial pathogens (Bogunovic et al, 2012; Morales and Lenschow, 2013b; Radoshevich et al, 2015; Speer et al, 2016; Zhang et al, 2015). In addition to its intracellular conjugation function and its extracellular signaling function, ISG15 has recently been shown to have an intracellular conjugation-independent function in modulating a non-catalytic function of USP18 (Zhang et al, 2015); this activity of USP18 directly regulates signaling through the Type I interferon receptor.…”

Section: Discussionmentioning

confidence: 99%

Extracellular ISG15 Signals Cytokine Secretion through the LFA-1 Integrin Receptor

et al. 2017

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Summary ISG15 is a ubiquitin-like protein that functions in innate immunity both as an intracellular protein modifier and as an extracellular signaling molecule that stimulates IFN-γ secretion. The extracellular function, important for resistance to mycobacterial disease, has remained biochemically uncharacterized. We have established an NK-92 cell-based assay for IFN-γ release, identified residues critical for ISG15 signaling, and identified the cell surface receptor as LFA-1 (CD11a/CD18; αLβ2 integrin). LFA-1 inhibition blocked IFN-γ secretion, splenocytes from CD11a−/− mice did not respond to ISG15, and ISG15 bound directly to the αI domain of CD11a in vitro. ISG15 also enhanced secretion of IL-10, indicating a broader role for ISG15 in cytokine signaling. ISG15 engagement of LFA-1 led to activation of SRC family kinases (SFKs) and SFK inhibition blocked cytokine secretion. These findings establish the molecular basis of the extracellular function of ISG15 and the initial “outside-in” signaling events that drive ISG15-dependent cytokine secretion.

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Section: Discussionmentioning

confidence: 99%

Extracellular ISG15 Signals Cytokine Secretion through the LFA-1 Integrin Receptor

et al. 2017

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“…The ISG USP18, a negative regulator of interferon signaling (40), is stabilized by ISG15, and their abundances are correlated (41). USP18 is proviral toward many viruses, including HCMV (14). ISG15 accumulation early during infection might stabilize USP18, curtailing cell-intrinsic immune responses later in infection.…”

Section: Discussionmentioning

confidence: 99%

Restriction of Human Cytomegalovirus Replication by ISG15, a Host Effector Regulated by cGAS-STING Double-Stranded-DNA Sensing

Bianco

Mohr

2017

J Virol

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Accumulation of the interferon-stimulated gene 15 (ISG15) protein product, which is reversibly conjugated to numerous polypeptide targets, impacts the proteome and physiology of uninfected and infected cells. While many viruses, including human cytomegalovirus (HCMV), blunt host antiviral defenses by limiting ISG expression, the overall abundance of ISG15 monomer and protein conjugates rises in HCMV-infected cells. However, the molecular signals underlying ISG15 accumulation and whether the ISG15 polypeptide itself influences HCMV infection biology remain unknown. Here, we establish that the ISG15 gene product itself directly regulates HCMV replication and that its accumulation restricts productive virus growth. Although ISG15 monomer and protein conjugate accumulation was induced in cells infected with UV-inactivated HCMV, it was subsequently reduced, but not eliminated, by an immediate-early (IE) or early (E) virus-encoded function(s). Instead, HCMV-induced ISG15 monomer and protein conjugate accumulation was dependent upon the double-stranded DNA (dsDNA) sensor cyclic GMP-AMP synthase (cGAS), the innate immune adaptor STING, and interferon signaling. Significantly, dsDNA itself was sufficient to induce cGAS-, STING-, and interferon signaling-dependent ISG15 monomer and conjugate protein accumulation in uninfected cells. Accumulation of ISGylated proteins in uninfected cells treated with dsDNA was prevented by expressing the HCMV multifunctional IE1 transactivator. This demonstrates that expression of a single host interferon-stimulated gene, ISG15, restricts HCMV replication, and that IE1 is sufficient to blunt ISGylation in response to dsDNA sensing in uninfected cells. Moreover, it establishes that ISGylation modifies the proteomes of virus-infected and uninfected normal cells in response to cell-intrinsic dsDNA sensing dependent upon cGAS-STING.IMPORTANCE By antagonizing type I interferon production and action, many viruses, including human cytomegalovirus (HCMV), evade host defenses. However, levels of the interferon-induced ISG15 protein, which is covalently conjugated to host and viral proteins, increase in HCMV-infected cells. How ISG15 accumulation is regulated and whether the ISG15 polypeptide influences HCMV replication remain unknown. This study establishes that ISG15 itself restricts HCMV replication and that HCMV-induced ISG15 accumulation is triggered by host defenses that detect cytoplasmic double-stranded DNA (dsDNA). Remarkably, dsDNA triggered ISG15 accumulation even in uninfected cells, and this was reduced by HCMV IE1 expression. This shows that ISG15 itself controls the replication of HCMV, which causes life-threatening disease among the immunocompromised and is a significant source of congenital morbidity and mortality among newborns. Moreover, it demonstrates that ISG15 modifies the uninfected cell proteome in response to dsDNA, potentially impacting responses to DNA vaccines, gene therapy, and autoimmune disease pathogenesis.

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“…For instance, human ubiquitin-specific peptidase 18 (USP18) negatively regulates type-I IFN signaling by binding to the IFN receptor. Human ISG15 stabilizes USP18 and thus is part of this negative feedback, while no equivalent feedback exists in mice (Speer et al, 2016). ISG15 displays various antiviral functions, both as a secreted protein and upon conjugation.…”

Section: Introductionmentioning

confidence: 99%

Crimean-Congo Hemorrhagic Fever Virus Suppresses Innate Immune Responses via a Ubiquitin and ISG15 Specific Protease

et al. 2017

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SUMMARY Antiviral responses are regulated by conjugation of ubiquitin (Ub) and interferon-stimulated gene 15 (ISG15) to proteins. Certain classes of viruses encode Ub- or ISG15-specific proteases belonging to the ovarian tumor (OTU) superfamily. Their activity is thought to suppress cellular immune responses, but studies demonstrating the function of viral OTU proteases during infection are lacking. Crimean-Congo hemorrhagic fever virus (CCHFV, family Nairoviridae) is a highly pathogenic human virus that encodes an OTU with both deubiquitinase and deISGylase activity as part of the viral RNA polymerase. We investigated CCHFV OTU function by inactivating protease catalytic activity or by selectively disrupting its deubiquitinase and deISGylase activity using reverse genetics. CCHFV OTU inactivation blocked viral replication independently of its RNA polymerase activity, while deubiquitinase activity proved critical for suppressing the interferon responses. Our findings provide insights into viral OTU functions and supports the development of therapeutics and vaccines.

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ISG15 deficiency and increased viral resistance in humans but not mice

Cited by 167 publications

References 59 publications

Extracellular ISG15 Signals Cytokine Secretion through the LFA-1 Integrin Receptor

Extracellular ISG15 Signals Cytokine Secretion through the LFA-1 Integrin Receptor

Restriction of Human Cytomegalovirus Replication by ISG15, a Host Effector Regulated by cGAS-STING Double-Stranded-DNA Sensing

Crimean-Congo Hemorrhagic Fever Virus Suppresses Innate Immune Responses via a Ubiquitin and ISG15 Specific Protease

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