文摘
We have identified a novel human interferon, designated as interferon-¦Ë4 (IFN-¦Ë4) (Prokunina-Olsson et al., Nature Genetics, 2013). Inducible expression of IFNL4, along with three related genes (IFNL1, IFNL2 and IFNL3) located on chromosome 19q13.13 and encoding other interferon-¦Ë proteins, IFN-¦Ë1, IFN-¦Ë2 and IFN-¦Ë3, was revealed by RNA-sequencing in primary human hepatocytes treated with polyI:C. In humans, IFN-¦Ë4 is fully genetically controlled - it is produced only by mRNA transcripts with a frameshift dG allele of a genetic variant ss469415590 (TT/dG) within the first exon of the gene, while transcripts with the TT allele can generate only unrelated proteins or protein fragments. We characterized IFN-¦Ë4 as a class-2 cytokine based on its protein homology with IFN-¦Ë3 (29 % amino acid identity), the ability to cause STAT1 and STAT2 phosphorylation, activation of an ISRE-Luc reporter, induction of ISGs and antiviral response in HepG2 cells transiently transfected with an IFNL4-expressing construct. IFN-¦Ë4 signaling is decreased by a JAK inhibitor, siRNA-silencing of IFN-¦ËR1, and blocking of IL10R2. However, HepG2 cells did not respond to treatment with purified recombinant IFN-¦Ë4 protein. Protein expression of IFN-¦Ë4 is detectable in cells transfected with an IFNL4-expressing construct but not in the culture supernatants. It remains unclear whether IFN-¦Ë4 is an unusual intracellular interferon, which signals through yet unknown intracellular partners or it is released at low levels through secretion or other mechanisms. Individuals homozygous for the derived human-specific ss469415590-TT allele (90 % of Asians, 50 % of Europeans and 10 % of individuals of African ancestry) are genetically unable to produce IFN-¦Ë4. This pattern suggests strong positive selection for elimination of IFN-¦Ë4, which might be caused by current or historic infectious diseases. Individuals who are unable to produce IFN-¦Ë4 are more likely to clear hepatitis C virus (HCV) either spontaneously or after treatment with IFN-¦Á and ribavirin.
