Acetaldehyde Disrupts Interferon Alpha Signaling in Hepatitis C Virus‐Infected Liver Cells by Up‐Regulating <scp>USP</scp>18

Ganesan, Murali; Poluektova, Larisa Y.; Tuma, Dean J.; Kharbanda, Kusum K.; Osna, Natalia A.

doi:10.1111/acer.13226

Cited by 42 publications

(37 citation statements)

References 33 publications

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“…The ISGylation of interferon regulatory factor 3 (IRF3) and STAT1 interferes with ubiquitylation and subsequent degradation of these proteins 79,84 . IRF3 is a transcription factor that, once phosphorylated, moves from the cytoplasm to the nucleus to form a complex with CREB-binding protein (CREBBP) and activates the transcription of IFNα, IFNβ and additional ISGs.…”

Section: Box 1 | Insights Into Isg15 Functions From Isg15-deficient Imentioning

confidence: 99%

“…The level of U-ISGF3 is significantly increased in response to IFNλ and IFNβ during chronic HCV infection and sustains the expression of ISG15 and a subset of ISGs, which restricts HCV replication. The sustained ISG15 expression led to stabilization of USP18 levels, which decreased signalling through the type I interferon receptor 84,89 . Therefore, the regulation of interferon signalling that is mediated by ISG15 contributes to the maintenance of chronic HCV.…”

Section: Box 1 | Insights Into Isg15 Functions From Isg15-deficient Imentioning

confidence: 99%

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ISG15 in antiviral immunity and beyond

2018

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The host response to viral infection includes the induction of type I interferons and the subsequent upregulation of hundreds of interferon-stimulated genes. Ubiquitin-like protein ISG15 is an interferon-induced protein that has been implicated as a central player in the host antiviral response. Over the past 15 years, efforts to understand how ISG15 protects the host during infection have revealed that its actions are diverse and pathogen-dependent. In this Review, we describe new insights into how ISG15 directly inhibits viral replication and discuss the recent finding that ISG15 modulates the host damage and repair response, immune response and other host signalling pathways. We also explore the viral immune-evasion strategies that counteract the actions of ISG15. These findings are integrated with a discussion of the recent identification of ISG15-deficient individuals and a cellular receptor for ISG15 that provides new insights into how ISG15 shapes the host response to viral infection.

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Section: Box 1 | Insights Into Isg15 Functions From Isg15-deficient Imentioning

confidence: 99%

Section: Box 1 | Insights Into Isg15 Functions From Isg15-deficient Imentioning

confidence: 99%

ISG15 in antiviral immunity and beyond

2018

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“…The effects of free ISG15 and ISGylation on cell biology are diverse and can be stimulatory as well as inhibitory. ISGylation can enhance antiviral signaling pathways by prolonging the activation state of signaling proteins (e.g., IRF3, STAT1), resulting in a higher production of type I IFN and ISGs [23,24]. Although ISG15 plays an important role activating antiviral immunity, it also provides negative feedback suppression of antiviral signaling pathways.…”

Section: The Intracellular Role Of Isg15mentioning

confidence: 99%

ISG15: It's Complicated

Dzimianski

Scholte

Bergeron

et al. 2019

Journal of Molecular Biology

126

114

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Interferon-stimulated gene product 15 (ISG15) is a key component of host responses to microbial infection. Despite having been known for four decades, grasping the functions and features of ISG15 has been a slow and elusive process. Substantial work over the past two decades has greatly enhanced this understanding, revealing the complex and variable nature of this protein. This has unveiled multiple mechanisms of action that are only now beginning to be understood. In addition, it has uncovered diversity not only between how ISG15 affects different pathogens but also between the function and structure of ISG15 itself between different host species. Here we review the complexity of ISG15 within the context of viral infection, focusing primarily on its antiviral function and the mechanisms viruses employ to thwart its effects. We highlight what is known regarding the impact of ISG15 sequence and structural diversity on these interactions and discuss the aspects presenting the next frontier toward elucidating a more complete picture of ISG15 function.

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“…ISGylation appears to be largely restricted to newly synthesized proteins due to HERC5 ribosomal association, thus making ISGs and viral proteins central targets (19)(20)(21). ISGylation can exert antiviral activity by prolonging antiviral signaling (IRF3, STAT) (22,23) or by interfering with the function of viral proteins. For example, ISGylation can interfere with oligomerization of viral proteins, which is important for the formation of viral particles and ribonucleoprotein (RNP) complexes (19,24).…”

mentioning

confidence: 99%

Stable Occupancy of the Crimean-Congo Hemorrhagic Fever Virus-Encoded Deubiquitinase Blocks Viral Infection

Scholte

Hua

Spengler

et al. 2019

mBio

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Crimean-Congo hemorrhagic fever virus (CCHFV) infection can result in a severe hemorrhagic syndrome for which there are no antiviral interventions available to date. Certain RNA viruses, such as CCHFV, encode cysteine proteases of the ovarian tumor (OTU) family that antagonize interferon (IFN) production by deconjugating ubiquitin (Ub). The OTU of CCHFV, a negative-strand RNA virus, is dispensable for replication of the viral genome, despite being part of the large viral RNA polymerase. Here, we show that mutations that prevent binding of the OTU to cellular ubiquitin are required for the generation of recombinant CCHFV containing a mutated catalytic cysteine. Similarly, the high-affinity binding of a synthetic ubiquitin variant (UbV-CC4) to CCHFV OTU strongly inhibits viral growth. UbV-CC4 inhibits CCHFV infection even in the absence of intact IFN signaling, suggesting that its antiviral activity is not due to blocking the OTU’s immunosuppressive function. Instead, the prolonged occupancy of the OTU with UbV-CC4 directly targets viral replication by interfering with CCHFV RNA synthesis. Together, our data provide mechanistic details supporting the development of antivirals targeting viral OTUs. IMPORTANCE Crimean-Congo hemorrhagic fever virus is an important human pathogen with a wide global distribution for which no therapeutic interventions are available. CCHFV encodes a cysteine protease belonging to the ovarian tumor (OTU) family which is involved in host immune suppression. Here we demonstrate that artificially prolonged binding of the OTU to a substrate inhibits virus infection. This provides novel insights into CCHFV OTU function during the viral replicative cycle and highlights the OTU as a potential antiviral target.

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Acetaldehyde Disrupts Interferon Alpha Signaling in Hepatitis C Virus‐Infected Liver Cells by Up‐Regulating USP18

Cited by 42 publications

References 33 publications

ISG15 in antiviral immunity and beyond

ISG15 in antiviral immunity and beyond

ISG15: It's Complicated

Stable Occupancy of the Crimean-Congo Hemorrhagic Fever Virus-Encoded Deubiquitinase Blocks Viral Infection

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