Zinc is a potent and specific inhibitor of IFN-λ3 signalling

Nature Communications
Scott A ReadGolo Ahlenstiel

Abstract

Lambda interferons (IFNL, IFN-λ) are pro-inflammatory cytokines important in acute and chronic viral infection. Single-nucleotide polymorphisms rs12979860 and rs8099917 within the IFNL gene locus predict hepatitis C virus (HCV) clearance, as well as inflammation and fibrosis progression in viral and non-viral liver disease. The underlying mechanism, however, is not defined. Here we show that the rs12979860 CC genotype correlates with increased hepatic metallothionein expression through increased systemic zinc levels. Zinc interferes with IFN-λ3 binding to IFNL receptor 1 (IFNLR1), resulting in decreased antiviral activity and increased viral replication (HCV, influenza) in vitro. HCV patients with high zinc levels have low hepatocyte antiviral and inflammatory gene expression and high viral loads, confirming the inhibitory role of zinc in vivo. We provide the first evidence that zinc can act as a potent and specific inhibitor of IFN-λ3 signalling and highlight its potential as a target of therapeutic intervention for IFN-λ3-mediated chronic disease.

Associated Datasets

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Citations

Oct 25, 2017·International Journal of Molecular Sciences·Martina MaywaldLothar Rink
Dec 15, 2017·Journal of Viral Hepatitis·S A ReadG Ahlenstiel
Oct 27, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Adeola A ObajemuOlusegun O Onabajo
Jun 14, 2018·DNA and Cell Biology·Nidhi KaushikMilan Surjit
Jun 22, 2018·American Journal of Physiology. Gastrointestinal and Liver Physiology·Liu LiuZijuan Liu
Apr 24, 2019·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Mohammed EslamJacob George
Jan 23, 2020·International Journal of Molecular Sciences·Dangdang LiGuangchao Sui
Jun 5, 2019·Journal of Biomedical Materials Research. Part a·Bailong TaoKaiyong Cai
Jul 16, 2019·Advances in Nutrition·Scott A ReadGolo Ahlenstiel
Dec 10, 2020·Metallomics : Integrated Biometal Science·Jemmyson Romário de Jesus, Tatianny de Araújo Andrade
Feb 5, 2021·Frontiers in Cellular Neuroscience·Maude BordeleauMarie-Ève Tremblay
Dec 1, 2020·Pharmacology & Therapeutics·Bingjian WenZhengquan Su
Aug 1, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Apu ChowdhurySicen Wang
Aug 10, 2021·Biological Trace Element Research·Fatemeh SadeghsoltaniMostafa Vaghari-Tabari
Sep 2, 2021·Journal of Medical Microbiology·Kate Chander Chiang, Ajay Gupta
Oct 8, 2021·Cellular Microbiology·Aleksha PanwarGuruprasad R Medigeshi
Dec 3, 2021·Mass Spectrometry Reviews·Rutuja H PatilVladimír Havlíček

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Datasets Mentioned

BETA
GSE54648

Methods Mentioned

BETA
Flow cytometry
co-immunoprecipitation
co-IP
proximity ligation assay
genotyping
ELISA
PCR
electrophoresis
proximity ligation
biopsy

Software Mentioned

Dryad
XCalibur Qual Browser
Beadstudio
GraphPad Prism
UCSC genome browser
Proteome Discoverer
ImageJ
Mascot

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