Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation

Zhang, Xianqin; Bogunovic, Dusan; Payelle-Brogard, Béatrice; François-Newton, Véronique; Speer, Scott D.; Yuan, Chao; Volpi, Stefano; Li, Zhi; Sanal, Özden; Mansouri, Davood; Tezcan, İlhan; Rice, Gillian I.; Chen, Chun-Yuan; Mansouri, Nahal; Mahdaviani, Seyed Alireza; Itan, Yuval; Boisson, Bertrand; Okada, Satoshi; Zeng, Lu; Wang, Xing; Jiang, Hui; Liu, Wenqiang; Han, Tiantian; Liu, Delin; Ma, Tao; Wang, Bo; Liu, Mugen; Liu, Jingyu; Wang, Qing Kenneth; Yalnızoğlu, Dilek; Radoshevich, Lilliana; Uzé, Gilles; Gros, Philippe; Rozenberg, Flore; Zhang, Shen-Ying; Jouanguy, Emmanuelle; Bustamante, Jacinta; García‐Sastre, Adolfo; Abel, Laurent; Lebon, Pierre; Notarangelo, Luigi D.; Crow, Yanick J.; Boisson–Dupuis, Stéphanie; Casanova, Jean‐Laurent; Pellegrini, Sandra

doi:10.1038/nature13801

Cited by 477 publications

(533 citation statements)

References 31 publications

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“…Another possibility is that ISG15 monomer and protein conjugate accumulation may inhibit ISG expression and/or the functions of ISG products at later times during infection. 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).…”

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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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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“…In humans, ISG15 dysregulation is associated with neuroinflammatory disease (2,40). Zebrafish isg15 is also activated after viral stimulation (18), and it has been shown to be a key regulator of IFN-mediated antiviral responses (41).…”

Section: Discussionmentioning

confidence: 99%

Characterization of samhd1 Morphant Zebrafish Recapitulates Features of the Human Type I Interferonopathy Aicardi-Goutières Syndrome

Kasher

Jenkinson

Briolat

et al. 2015

The Journal of Immunology

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In humans, loss of function mutations in the SAMHD1 (AGS5) gene cause a severe form of Aicardi-Goutières syndrome (AGS), an inherited inflammatory-mediated encephalopathy characterized by increased type I IFN activity and upregulation of IFN-stimulated genes (ISGs). In particular, SAMHD1-related AGS is associated with a distinctive cerebrovascular pathology that commonly leads to stroke. Although inflammatory responses are observed in immune cells cultured from Samhd1 null mouse models, these mice are physically healthy, specifically lacking a brain phenotype. We have investigated the use of zebrafish as an alternative system for generating a clinically relevant model of SAMHD1-related AGS. Using temporal gene knockdown of zebrafish samhd1, we observe hindbrain ventricular swelling and brain hemorrhage. Furthermore, loss of samhd1 or of another AGS-associated gene, adar, leads to a significant upregulation of innate immune-related genes and an increase in the number of cells expressing the zebrafish type I IFN ifnphi1. To our knowledge, this is the first example of an in vivo model of AGS that recapitulates features of both the innate immune and neurological characteristics of the disease. The phenotypes associated with loss of samhd1 and adar suggest a function of these genes in controlling innate immune processes conserved to zebrafish, thereby also contributing to our understanding of antiviral signaling in this model organism.

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“…As a mechanism of the unresponsiveness to IFN-α, we further investigated ISG15, one of the U-ISGs. ISG15 was recently shown to regulate the stability of the USP18 protein by preventing its ubiquitination (27), and USP18 is a well-known negative regulator of IFN-α signaling. We hypothesized that prolonged stimulation with IFN-λ induces U-ISGF3 and U-ISGs, including ISG15, and that subsequent stabilization of USP18 by ISG15 confers lack of response to exogenous IFN-α.…”

Section: The Expression Of Isg15 and Usp18 Proteins Is Increased By Pmentioning

confidence: 99%

Roles of unphosphorylated ISGF3 in HCV infection and interferon responsiveness

Sung

Cheon

Cho

et al. 2015

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

105

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Up-regulation of IFN-stimulated genes (ISGs) is sustained in hepatitis C virus (HCV)-infected livers. Here, we investigated the mechanism of prolonged ISG expression and its role in IFN responsiveness during HCV infection in relation to unphosphorylated IFN-stimulated gene factor 3 (U-ISGF3), recently identified as a tripartite transcription factor formed by high levels of IFN response factor 9 (IRF9), STAT1, and STAT2 without tyrosine phosphorylation of the STATs. The level of U-ISGF3, but not tyrosine phosphorylated STAT1, is significantly elevated in response to IFN-λ and IFN-β during chronic HCV infection. U-ISGF3 prolongs the expression of a subset of ISGs and restricts HCV chronic replication. However, paradoxically, high levels of U-ISGF3 also confer unresponsiveness to IFN-α therapy. As a mechanism of U-ISGF3-induced resistance to IFN-α, we found that ISG15, a U-ISGF3-induced protein, sustains the abundance of ubiquitin-specific protease 18 (USP18), a negative regulator of IFN signaling. Our data demonstrate that U-ISGF3 induced by IFN-λs and -β drives prolonged expression of a set of ISGs, leading to chronic activation of innate responses and conferring a lack of response to IFN-α in HCVinfected liver.hepatitis C virus | U-ISGF3 | interferon | interferon-stimulated genes

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Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation

Cited by 477 publications

References 31 publications

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

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

Characterization of samhd1 Morphant Zebrafish Recapitulates Features of the Human Type I Interferonopathy Aicardi-Goutières Syndrome

Roles of unphosphorylated ISGF3 in HCV infection and interferon responsiveness

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