Hepatic <i>IFNL4</i> expression is associated with non‐response to interferon‐based therapy through the regulation of basal interferon‐stimulated gene expression in chronic hepatitis C patients

Murakawa, Miyako; Asahina, Yasuhiro; Kawai‐Kitahata, Fukiko; Nakagawa, Mina; Nitta, Sayuri; Otani, Satoshi; Nagata, Hiroko; Kaneko, Shun; Asano, Yoshihiro; Tsunoda, Tomoyuki; Miyoshi, Masato; Itsui, Yasuhiro; Azuma, Seishin; Kakinuma, Sei; Tanaka, Yasuhito; Iijima, Sayuki; Tsuchiya, Kaoru; Izumi, Namiki; Tohda, Shuji; Watanabe, Mamoru

doi:10.1002/jmv.24763

Cited by 10 publications

(5 citation statements)

References 43 publications

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“…By quantifying the IFNL4 transcripts in liver biopsy specimens from a broad panel of various different nonmalignant liver disorders, we found IFNL4 transcripts (i) detectable exclusively in hepatitis C patients, (ii) their total number to be correlated to hepatic viral load, and (iii) the number of functional but not that of nonfunctional transcripts to be associated with the activation of ISGs [16]. These data, together with affirming findings by others [17,18], are suggestive for HCV being an activator of IFNL4 transcription in human liver, fostering an IFN signature in those individuals who carry the functional IFNL4 variant. Yet, they demand validation.…”

Section: Introductionsupporting

confidence: 87%

Hepatic IFNL4 Gene Activation in Hepatocellular Carcinoma Patients with Regard to Etiology

Huschka

Mihm

2021

IJMS

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Hepatocellular carcinoma (HCC) is a malignancy with a leading lethality. The etiology is quite diverse, ranging from viral infections to metabolic disorders or intoxications, and associates with specific somatic mutational patterns and specific host immunological phenotypes. Particularly, hepatitis C virus (HCV)-infected liver is featured by an activation of interferon (IFN)-stimulated genes (ISGs; IFN signature), which we suppose is driven by type III IFNL4. Taking advantage of the TCGA collection of HCC patients of various different etiologies, this study aimed at validating our previous findings on hepatic IFNL4 gene activation in HCV infection in an independent and larger cohort of patients with advanced liver disease. In a cohort of n = 377 cases, the entirety of the sequencing data was used to assess the IFNL genotypes, and the cases were stratified for etiology. The number of IFNL4 transcripts within nonmalignant and malignant tissues was found to be more abundant in patients with HCV or HCV/HBV infections when compared to other risk factors. Moreover, in patients with HCV infection as a risk factor, a close, positive relationship was found between ISG activation and the number of functional IFNL4 transcripts. Data on this independent TCGA sample support the concept of an IFNL4-dependent HCV-driven activation of hepatic ISGs. In addition to that, they add to the understanding of etiology-related host immunological phenotypes in HCC.

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Section: Introductionsupporting

confidence: 87%

Hepatic IFNL4 Gene Activation in Hepatocellular Carcinoma Patients with Regard to Etiology

Huschka

Mihm

2021

IJMS

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“…Expression of IFNL4 mRNA was not detected in peripheral blood mononuclear cells from chronically infected HCV patients (24). Similarly, several other studies measured either no or very low IFNL4 mRNA expression in liver samples from patients with nonviral liver disease, chronic hepatitis B virus infection, or chronic HCV infection (25)(26)(27). Finally, both stimulation with pathogenassociated molecular patterns (PAMP) and viral infection of different hepatoma cell lines or primary human hepatocytes resulted in minimal expression of IFNL4 but strong expression of the canonical IFNL3 (28).…”

mentioning

confidence: 90%

The IFNL4 Gene Is a Noncanonical Interferon Gene with a Unique but Evolutionarily Conserved Regulation

Zhou

Møhlenberg

Terczyńska-Dyla

et al. 2020

J Virol

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Interferon lambda 4 (IFN-λ4) is a recently identified enigmatic member of the interferon (IFN) lambda family. Genetic data suggest that the IFNL4 gene acts in a proviral and anti-inflammatory manner in patients. However, the protein is indistinguishable in vitro from the other members of the interferon lambda family. We have investigated the gene regulation of IFNL4 in detail and found that it differs radically from that of canonical antiviral interferons. Being induced by viral infection is a defining characteristic of interferons, but viral infection or overexpression of members of the interferon regulatory factor (IRF) family of transcription factors only leads to a minute induction of IFNL4. This behavior is evolutionarily conserved and can be reversed by inserting a functional IRF3 binding site into the IFNL4 promoter. Thus, the regulation of the IFNL4 gene is radically different and might explain some of the atypical phenotypes associated with the IFNL4 gene in humans. IMPORTANCE Recent genetic evidence has highlighted how the IFNL4 gene acts in a counterintuitive manner, as patients with a nonfunctional IFNL4 gene exhibit increased clearance of hepatitis C virus (HCV) but also increased liver inflammation. This suggests that the IFNL4 gene acts in a proviral and anti-inflammatory manner. These surprising but quite clear genetic data have prompted an extensive examination of the basic characteristics of the IFNL4 gene and its gene product, interferon lambda 4 (IFN-λ4). We have investigated the expression of the IFNL4 gene and found it to be poorly induced by viral infections. A thorough investigation of the IFNL4 promoter revealed a highly conserved and functional promoter, but also one that lacks the defining characteristic of interferons (IFNs), i.e., the ability to be effectively induced by viral infections. We suggest that the unique function of the IFNL4 gene is related to its noncanonical transcriptional regulation.

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“…Additionally, extracellular ISG15 has several immunomodulatory activities such as the induction of natural killer cell proliferation and the stimulation of IFNproduction, triggering a type II IFN response (Bogunovic et al, 2012). ISG15 has also been linked to effective antiviral type III IFN responses (Shen et al, 2016;Murakawa et al, 2017;Fan et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Structure of interferon-stimulated gene product 15 (ISG15) from the bat species Myotis davidii and the impact of interdomain ISG15 interactions on viral protein engagement

Langley

Goodwin

Dzimianski

et al. 2019

Acta Cryst Sect D Struct Biol

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Bats have long been observed to be the hosts and the origin of numerous human diseases. Bats, like all mammals, rely on a number of innate immune mechanisms to combat invading pathogens, including the interferon type I, II and III responses. Ubiquitin-like interferon-stimulated gene product 15 (ISG15) is a key modulator of these interferon responses. Within these pathways, ISG15 can serve to stabilize host proteins modulating innate immune responses and act as a cytokine. Post-translational modifications of viral proteins introduced by ISG15 have also been observed to directly affect the function of numerous viral proteins. Unlike ubiquitin, which is virtually identical across all animals, comparison of ISG15s across species reveals that they are relatively divergent, with sequence identity dropping to as low as $58% among mammals. In addition to serving as an obstacle to the zoonotic transmission of influenza, these ISG15 species-species differences have also long been shown to have an impact on the function of viral deISGylases. Recently, the structure of the first nonhuman ISG15, originating from mouse, suggested that the structures of human ISG15 may not be reflective of other species. Here, the structure of ISG15 from the bat species Myotis davidii solved to 1.37 Å resolution is reported. Comparison of this ISG15 structure with those from human and mouse not only underscores the structural impact of ISG15 species-species differences, but also highlights a conserved hydrophobic motif formed between the two domains of ISG15. Using the papain-like deISGylase from Severe acute respiratory syndrome coronavirus as a probe, the biochemical importance of this motif in ISG15-protein engagements was illuminated.

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Hepatic IFNL4 expression is associated with non‐response to interferon‐based therapy through the regulation of basal interferon‐stimulated gene expression in chronic hepatitis C patients

Cited by 10 publications

References 43 publications

Hepatic IFNL4 Gene Activation in Hepatocellular Carcinoma Patients with Regard to Etiology

Hepatic IFNL4 Gene Activation in Hepatocellular Carcinoma Patients with Regard to Etiology

The IFNL4 Gene Is a Noncanonical Interferon Gene with a Unique but Evolutionarily Conserved Regulation

Structure of interferon-stimulated gene product 15 (ISG15) from the bat species Myotis davidii and the impact of interdomain ISG15 interactions on viral protein engagement

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