Crystal Structure of Human Interferon-λ1 in Complex with Its High-Affinity Receptor Interferon-λR1

Miknis, Zachary J.; Magracheva, Eugenia; Li, Wei; Zdanov, Alexander; Kotenko, Sergei V.; Wlodawer, Alexander

doi:10.1016/j.jmb.2010.09.068

Cited by 78 publications

(69 citation statements)

References 66 publications

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“…We noted that a P70S substitution (rs117648444) could potentially alter the activity of the protein, in addition this has a minor allele frequency (MAF) in Caucasian of 0.11 (HapMap), whereas the two other have 0 and 0.025, respectively. Proline 70 is located outside of the assumed receptor binding site 19,20 , but structural modelling suggests that P70 is important for the stability of the IFNl4 protein 17 . In the following, the two variants of IFNl4 will be denoted as IFNl4-P70 and IFNl4-S70, respectively.…”

Section: Resultsmentioning

confidence: 99%

Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes

et al. 2014

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Hepatitis C virus (HCV) infections are the major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide. Both spontaneous and treatment-induced clearance of HCV depend on genetic variation within the interferon-lambda locus, but until now no clear causal relationship has been established. Here we demonstrate that an amino-acid substitution in the IFNl4 protein changing a proline at position 70 to a serine (P70S) substantially alters its antiviral activity. Patients harbouring the impaired IFNl4-S70 variant display lower interferon-stimulated gene (ISG) expression levels, better treatment response rates and better spontaneous clearance rates, compared with patients coding for the fully active IFNl4-P70 variant. Altogether, these data provide evidence supporting a role for the active IFNl4 protein as the driver of high hepatic ISG expression as well as the cause of poor HCV clearance.

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Section: Resultsmentioning

confidence: 99%

Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes

et al. 2014

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“…The type III IFNs were termed interleukin-29 (IL-29)/IL-28A/IL-28B or IFN-1/IFN-2/IFN-3, respectively. IFN-s bind a novel heterodimeric class II cytokine receptor, with IFN-R1/ IL-28R␣ and IL-10R2/IL-10R␤ subunits (19). In some infections, including hepatitis C, type I IFNs are used for treatment.…”

Section: Importancementioning

confidence: 99%

Parainfluenza Virus 3 Blocks Antiviral Mediators Downstream of the Interferon Lambda Receptor by Modulating Stat1 Phosphorylation

Eberle

McGill

Reinhardt

et al. 2016

J Virol

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Parainfluenza viruses are known to inhibit type I interferon (IFN) production; however, there is a lack of information regarding the type III IFN response during infection. Type III IFNs signal through a unique heterodimeric receptor, IFN-R1/interleukin-10R2 (IL-10R2), which is primarily expressed by epithelial cells. Parainfluenza virus 3 (PIV-3) infection is highly restricted to the airway epithelium. We therefore sought to examine type III IFN signaling pathways during PIV-3 infection of epithelial cells. We used three strains of PIV-3: human PIV-3 (HPIV-3), bovine PIV-3 (BPIV-3), and dolphin PIV-1 (Tursiops truncatus PIV-1, or TtPIV-1). Here, we show that message levels of IL-29 are significantly increased during PIV-3 infection, yet downstream antiviral signaling molecules are not upregulated to levels similar to those of the positive control. IMPORTANCEParainfluenza virus (PIV) in humans is associated with bronchiolitis and pneumonia and can be especially problematic in infants and the elderly. Also seen in cattle, bovine PIV-3 causes respiratory infections in young calves. In addition, PIV-3 is one of a number of pathogens that contribute to the bovine respiratory disease complex (BRDC). As their name suggests, interferons (IFNs) are produced by cells to interfere with viral replication. Paramyxoviruses have previously been shown to block production and downstream signaling of type I IFNs. For the first time, it is shown here that PIV-3 can induce protective type III IFNs in epithelial cells, the primary site of PIV-3 infection. However, we found that PIV-3 modulates signaling pathways downstream of the type III IFN receptor to block production of several specific molecules that aid in a productive antiviral response. Importantly, this work expands our understanding of how PIV-3 effectively evades host innate immunity. P arainfluenza virus 3 (PIV-3) causes a prominent respiratory infection in both cattle and humans. The CDC reports that, in humans, most children have antibodies against human PIV-3 (HPIV-3) by 5 years of age (http://www.cdc.gov/parainfluenza /hcp/clinical.html). There is currently no vaccine available for control of HPIV-3 infection; however, a few studies have examined the use of an attenuated bovine PIV-3 (BPIV-3) to protect against HPIV-3 because of the homology between bovine and human strains (1-3). Given the lack of an efficacious vaccine for HPIV-3, there is a critical need to understand the mechanisms of HPIV-3-induced disease and the molecular pathways associated with viral modulation of the host antiviral defenses.Paramyoxviruses are negative-sense single-stranded RNA viruses which are part of the Paramyxoviridae family and Paramyxovirinae subfamily (4). PIV-3 is found within the genus Respirovirus. PIV-3 is a respiratory virus that primarily infects the epithelial cells of the lung. Symptoms of HPIV-3 infection include bronchiolitis and pneumonia, and HPIV-3 is especially problematic in infants (4). Airway epithelial cells recognize viral infection through pattern recog...

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“…The combination of IFN-λ and IL-28Rα induces a conformational change, which efficiently carries out the recruitment of IL-10R2 to the IFN-λ-IL-28Rα-IL-10R2 complex. The receptorassociated tyrosine kinases (TYK2 and JAK1) are then activated to control the tyrosine phosphorylation of the intracellular domain of the IL-28Rα chain [44,45]. STAT proteins track and bind to the motifs with phosphotyrosine in this domain and shape ISGF3, such as that of type I IFN.…”

Section: Ifn-λs Induction and Signal Pathwaysmentioning

confidence: 99%

Type III Interferons in Viral Infection and Antiviral Immunity

Zhou

Wang

Chang

et al. 2018

Cell Physiol Biochem

114

113

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Interferons (IFNs) can serve as the first line of immune defense against viral infection. The identification of IFN-λs 1, 2, 3 & 4 (termed as type III IFNs) has revealed that the antiviral immune response to viruses contains more components than the type I IFNs that have been known for more than 50 years. IFN-λs are IFN-λ1 (IL-29), IFN-λ2 (IL-28a), IFN-λ3 (IL-28b) and IFN-λ4, which resembles IFN-λ3. IFN-λs have type I-IFN-like immune responses and biological activities, but our knowledge of these novel players in the antiviral response is not well established. In this review, we try to describe the current information on the expression and function of IFN-λs in the innate antiviral immune defense and IFN-λ2’s role in regulating and shaping the adaptive immune response. We suggest that IFN-λs are key antiviral cytokines, directly performing an antiviral immune response at epithelial surfaces in the early stages of viral infection, and that these cytokines also skew the balance of Th1 and Th2 cells to Th1 phenotype. In addition, genetic polymorphisms in IFN-λ genes can impair antiviral immune responses in clinical treatment.

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Crystal Structure of Human Interferon-λ1 in Complex with Its High-Affinity Receptor Interferon-λR1

Cited by 78 publications

References 66 publications

Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes

Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes

Parainfluenza Virus 3 Blocks Antiviral Mediators Downstream of the Interferon Lambda Receptor by Modulating Stat1 Phosphorylation

Type III Interferons in Viral Infection and Antiviral Immunity

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