title: Interferon lambda 4 expression is suppressed by the host during viral infection.
abstract: Interferon (IFN) lambdas are critical antiviral effectors in hepatic and mucosal infections. Although IFNλ1, IFNλ2, and IFNλ3 act antiviral, genetic association studies have shown that expression of the recently discovered IFNL4 is detrimental to hepatitis C virus (HCV) infection through a yet unknown mechanism. Intriguingly, human IFNL4 harbors a genetic variant that introduces a premature stop codon. We performed a molecular and biochemical characterization of IFNλ4 to determine its role and regulation of expression. We found that IFNλ4 exhibits similar antiviral activity to IFNλ3 without negatively affecting antiviral IFN activity or cell survival. We show that humans deploy several mechanisms to limit expression of functional IFNλ4 through noncoding splice variants and nonfunctional protein isoforms. Furthermore, protein-coding IFNL4 mRNA are not loaded onto polyribosomes and lack a strong polyadenylation signal, resulting in poor translation efficiency. This study provides mechanistic evidence that humans suppress IFNλ4 expression, suggesting that immune function is dependent on other IFNL family members.
authors: Department of Immunology, University of Washington, Seattle, WA 98109.
authors: MeeAe
authors: M
authors: Hong
authors: Department of Immunology, University of Washington, Seattle, WA 98109.
authors: Johannes
authors: 0000-0002-5964-7162
authors: J
authors: Schwerk
authors: Department of Immunology, University of Washington, Seattle, WA 98109.
authors: Chrissie
authors: 0000-0002-1011-5720
authors: C
authors: Lim
authors: Department of Immunology, University of Washington, Seattle, WA 98109.
authors: Alison
authors: 0000-0001-5550-1038
authors: A
authors: Kell
authors: Department of Immunology, University of Washington, Seattle, WA 98109.
authors: Abigail
authors: 0000-0002-8864-9829
authors: A
authors: Jarret
authors: Department of Immunology, University of Washington, Seattle, WA 98109.
authors: Joseph
authors: 0000-0002-6046-614X
authors: J
authors: Pangallo
authors: Department of Immunology, University of Washington, Seattle, WA 98109.
authors: Yueh-Ming
authors: 0000-0001-6294-7273
authors: YM
authors: Loo
authors: Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT 84112.
authors: Shuanghu
authors: 0000-0001-5422-9466
authors: S
authors: Liu
authors: Department of Medicine, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR 72205.|Genetics Program, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR 72205.
authors: Curt H
authors: CH
authors: Hagedorn
authors: Department of Immunology, University of Washington, Seattle, WA 98109.
authors: Michael
authors: M
authors: Gale
authors: Department of Immunology, University of Washington, Seattle, WA 98109 savanram@uw.edu.
authors: Ram
authors: 0000-0002-3087-1355
authors: R
authors: Savan
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D005110:Extracellular Space / Q000378:metabolism; D016368:Frameshift Mutation / Q000235:genetics; D016174:Hepacivirus / Q000187:drug effects; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000378:metabolism* / Q000494:pharmacology; D042541:Intracellular Space / Q000378:metabolism; D008954:Models, Biological; D000069452:Pathogen-Associated Molecular Pattern Molecules / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism; D017471:Receptors, Interferon; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014777:Virus Diseases / Q000378:metabolism*; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D007372:Interferons; D007378:Interleukins; D000069452:Pathogen-Associated Molecular Pattern Molecules; D020033:Protein Isoforms; D018121:Receptors, Cytokine; D017471:Receptors, Interferon; D011994:Recombinant Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579163:IFNL4 protein, human; C579640:IFNLR1 protein, human