The Amino-Terminal Region of Hepatitis E Virus ORF1 Containing a Methyltransferase (Met) and a Papain-Like Cysteine Protease (PCP) Domain Counteracts Type I Interferon Response

Hepatitis E virus (HEV) is responsible for large waterborne epidemics of hepatitis in endemic countries and is an emerging zoonotic pathogen worldwide. In endemic regions, HEV-1 or HEV-2 genotypes are frequently associated with fulminant hepatitis in pregnant women, while with zoonotic HEV (HEV-3 and HEV-4), chronic cases of hepatitis and severe neurological disorders are reported. Hence, it is important to characterize the interactions between HEV and its host. Here, we investigated the ability of the non-structural polyprotein encoded by the first open reading frame (ORF1) of HEV to modulate the host early antiviral response and in particular the type I interferon (IFN-I) system. We found that the amino-terminal region of HEV-3 ORF1 (MetPCP), containing a putative methyltransferase (Met) and a papain-like cysteine protease (PCP) functional domain, inhibited IFN-stimulated response element (ISRE) promoter activation and the expression of several IFN-stimulated genes (ISGs) in response to IFN-I. We showed that the MetPCP domain interfered with the Janus kinase (JAK)/signal transducer and activator of transcription protein (STAT) signalling pathway by inhibiting STAT1 nuclear translocation and phosphorylation after IFN-I treatment. By contrast, MetPCP had no effect on STAT2 phosphorylation and a limited impact on the activation of the JAK/STAT pathway after IFN-II stimulation. This inhibitory function seemed to be genotype-dependent as MetPCP from HEV-1 had no significant effect on the JAK/STAT pathway. Overall, this study provides evidence that the predicted MetPCP domain of HEV ORF1 antagonises STAT1 activation to modulate the IFN response.

Download Full-text

The Amino-Terminal Region of Hepatitis E Virus ORF1 Containing a Methyltransferase (Met) and a Papain-Like Cysteine Protease (PCP) Domain Counteracts Type I Interferon Response

Viruses ◽

10.3390/v10120726 ◽

2018 ◽

Vol 10 (12) ◽

pp. 726 ◽

Cited By ~ 4

Author(s):

Eugénie Bagdassarian ◽

Virginie Doceul ◽

Marie Pellerin ◽

Antonin Demange ◽

Léa Meyer ◽

...

Keyword(s):

Cysteine Protease ◽

Hepatitis E Virus ◽

Type I Interferon ◽

Hepatitis E ◽

Terminal Region ◽

Janus Kinase ◽

Functional Domain ◽

Type I ◽

Amino Terminal ◽

Stat Pathway

Hepatitis E virus (HEV) is responsible for large waterborne epidemics of hepatitis in endemic countries and is an emerging zoonotic pathogen worldwide. In endemic regions, HEV-1 or HEV-2 genotypes are frequently associated with fulminant hepatitis in pregnant women, while with zoonotic HEV (HEV-3 and HEV-4), chronic cases of hepatitis and severe neurological disorders are reported. Hence, it is important to characterize the interactions between HEV and its host. Here, we investigated the ability of the nonstructural polyprotein encoded by the first open reading frame (ORF1) of HEV to modulate the host early antiviral response and, in particular, the type I interferon (IFN-I) system. We found that the amino-terminal region of HEV-3 ORF1 (MetYPCP), containing a putative methyltransferase (Met) and a papain-like cysteine protease (PCP) functional domain, inhibited IFN-stimulated response element (ISRE) promoter activation and the expression of several IFN-stimulated genes (ISGs) in response to IFN-I. We showed that the MetYPCP domain interfered with the Janus kinase (JAK)/signal transducer and activator of the transcription protein (STAT) signalling pathway by inhibiting STAT1 nuclear translocation and phosphorylation after IFN-I treatment. In contrast, MetYPCP had no effect on STAT2 phosphorylation and a limited impact on the activation of the JAK/STAT pathway after IFN-II stimulation. This inhibitory function seemed to be genotype-dependent, as MetYPCP from HEV-1 had no significant effect on the JAK/STAT pathway. Overall, this study provides evidence that the predicted MetYPCP domain of HEV ORF1 antagonises STAT1 activation to modulate the IFN response.

Download Full-text

Hepatitis E Virus Papain-Like Cysteine Protease Inhibits Type I Interferon Induction by Down-Regulating Melanoma Differentiation-Associated Gene 5

Journal of Microbiology and Biotechnology ◽

10.4014/jmb.1809.09028 ◽

2018 ◽

Vol 28 (11) ◽

pp. 1908-1915 ◽

Cited By ~ 7

Author(s):

Eunha Kim ◽

Jinjong Myoung

Keyword(s):

Cysteine Protease ◽

Hepatitis E Virus ◽

Type I Interferon ◽

Hepatitis E ◽

Type I ◽

Interferon Induction

Download Full-text

Hepatitis E virus infection activates signal regulator protein α to down-regulate type I interferon

Immunologic Research ◽

10.1007/s12026-015-8729-y ◽

2015 ◽

Vol 64 (1) ◽

pp. 115-122 ◽

Cited By ~ 8

Author(s):

Fen Huang ◽

Chenchen Yang ◽

Wenhai Yu ◽

Yanhong Bi ◽

Feiyan Long ◽

...

Keyword(s):

Virus Infection ◽

Hepatitis E Virus ◽

Type I Interferon ◽

Hepatitis E ◽

Type I ◽

Regulator Protein

Download Full-text

Hepatitis E Virus Methyltransferase Inhibits Type I Interferon Induction by Targeting RIG-I

Journal of Microbiology and Biotechnology ◽

10.4014/jmb.1808.08058 ◽

2018 ◽

Vol 28 (9) ◽

pp. 1554-1562 ◽

Cited By ~ 8

Author(s):

Sangmin Kang ◽

Changsun Choi ◽

Insoo Choi ◽

Guinam Han ◽

Seong Woon Rho ◽

...

Keyword(s):

Hepatitis E Virus ◽

Type I Interferon ◽

Hepatitis E ◽

Type I ◽

Interferon Induction

Download Full-text

SARS-CoV-2 disrupts proximal elements in the JAK-STAT pathway

Journal of Virology ◽

10.1128/jvi.00862-21 ◽

2021 ◽

Author(s):

Da-Yuan Chen ◽

Nazimuddin Khan ◽

Brianna J. Close ◽

Raghuveera K. Goel ◽

Benjamin Blum ◽

...

Keyword(s):

Cell Lines ◽

Human Cell ◽

Type I Interferon ◽

Cell Types ◽

Janus Kinase ◽

Type I ◽

Human Cell Lines ◽

Interferon Signaling ◽

Interferon Receptor ◽

Stat Pathway

SARS-CoV-2 can infect multiple organs, including lung, intestine, kidney, heart, liver, and brain. The molecular details of how the virus navigates through diverse cellular environments and establishes replication are poorly defined. Here, we generated a panel of phenotypically diverse, SARS-CoV-2-infectable human cell lines representing different body organs and performed longitudinal survey of cellular proteins and pathways broadly affected by the virus. This revealed universal inhibition of interferon signaling across cell types following SARS-CoV-2 infection. We performed systematic analyses of the JAK-STAT pathway in a broad range of cellular systems, including immortalized cells and primary-like cardiomyocytes, and found that SARS-CoV-2 targeted the proximal pathway components, including Janus kinase 1 (JAK1), tyrosine kinase 2 (Tyk2), and the interferon receptor subunit 1 (IFNAR1), resulting in cellular desensitization to type I IFN. Detailed mechanistic investigation of IFNAR1 showed that the protein underwent ubiquitination upon SARS-CoV-2 infection. Furthermore, chemical Inhibition of JAK kinases enhanced infection of stem cell-derived cultures, indicating that the virus benefits from inhibiting the JAK-STAT pathway. These findings suggest that the suppression of interferon signaling is a mechanism widely used by the virus to evade antiviral innate immunity, and that targeting the viral mediators of immune evasion may help block virus replication in patients with COVID-19. IMPORTANCE SARS-CoV-2 can infect various organs in the human body, but the molecular interface between the virus and these organs remains unexplored. In this study, we generated a panel of highly infectable human cell lines originating from various body organs and employed these cells to identify cellular processes commonly or distinctly disrupted by SARS-CoV-2 in different cell types. One among the universally impaired processes was interferon signaling. Systematic analysis of this pathway in diverse culture systems showed that SARS-CoV-2 targets the proximal JAK-STAT pathway components, destabilizes the type I interferon receptor though ubiquitination, and consequently renders the infected cells resistant to type I interferon. These findings illuminate how SARS-CoV-2 can continue to propagate in different tissues even in the presence of a disseminated innate immune response.

Download Full-text

ISG15 Modulates Type I Interferon Signaling and the Antiviral Response during Hepatitis E Virus Replication

Journal of Virology ◽

10.1128/jvi.00621-17 ◽

2017 ◽

Vol 91 (19) ◽

Cited By ~ 18

Author(s):

Harini Sooryanarain ◽

Adam J. Rogers ◽

Dianjun Cao ◽

Mary Etna R. Haac ◽

Yogesh A. Karpe ◽

...

Keyword(s):

Hepatitis E Virus ◽

Acute Viral Hepatitis ◽

Type I Interferon ◽

Organ Transplant ◽

Clinical Problem ◽

Antiviral Effect ◽

Hepatitis E ◽

Type I ◽

Solid Organ ◽

Type I Ifn

ABSTRACT Hepatitis E virus (HEV), a single-stranded positive-sense RNA virus, generally causes self-limiting acute viral hepatitis, although chronic HEV infection has recently become a significant clinical problem in immunocompromised individuals, especially in solid-organ transplant recipients. Innate immunity, via the type I interferon (IFN) response, plays an important role during the initial stages of a viral infection. IFN-stimulated gene 15 (ISG15), an IFN-induced ubiquitin-like protein, is known to have an immunomodulatory role and can have a direct antiviral effect on a wide spectrum of virus families. In the present study, we investigated the antiviral effect as well as the potential immunomodulatory role of ISG15 during HEV replication. The results revealed that HEV induced high levels of ISG15 production both in vitro (Huh7-S10-3 liver cells) and in vivo (liver tissues from HEV-infected pigs); however, ISG15 is not required for virus replication. We also demonstrated that ISG15 silencing potentiates enhanced type I IFN-mediated signaling, resulting in an increase in the type I IFN-mediated antiviral effect during HEV replication. This observed enhanced type I IFN signaling correlated with an increase in IFN-stimulated gene expression levels during HEV replication. Furthermore, we showed that PKR and OAS1 played important roles in the ISG15-mediated type I IFN sensitivity of HEV. Taken together, the results from this study suggest that ISG15 plays an important immunomodulatory role and regulates HEV sensitivity to exogenous type I IFN. IMPORTANCE Hepatitis E virus (HEV) infection typically causes self-limiting acute viral hepatitis. However, chronic HEV infection has recently become a significant clinical problem in immunocompromised patients. Pegylated interferon (IFN) has been used to treat chronic HEV infection in solid-organ transplant patients with some success. However, the mechanism behind the type I IFN-mediated antiviral effect against HEV remains unclear. This report demonstrates that ISG15 induced by HEV replication in Huh7-S10-3 human liver cells plays an immunomodulatory role by negatively regulating type I IFN signaling and, thus, HEV sensitivity to type I IFN. Our results also show that PKR and OAS1 play important roles in the ISG15-mediated type I IFN sensitivity of HEV.

Download Full-text