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Interferon lambda 4 expression is suppressed by the host during viral infection
- 1Department of Immunology, University of Washington, Seattle, WA 98109.
- 2Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT 84112.
- 3Department of Medicine, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR 72205.
- 4Genetics Program, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR 72205.
- 5Department of Immunology, University of Washington, Seattle, WA 98109 email@example.com.
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.
© 2016 Hong et al.