110 : Characterization of the newly identified interferon Lambda 4

In 2009 genome-wide association studies identified the rs12979860 and rs8099917 SNPs on chromosome 19q13.13 near the interferon lambda ( IFN-λ3 ) gene as variants associated with both spontaneous Hepatitis C virus (HCV) clearance and response to pegIFN- α /RBV treatment [1,2]. Recently a dinucleotide variant, denoted ss469415590 (TT > DG) was discovered upstream of IFN-λ3 . The DG variant leads to a new open reading frame encoding a new member of the type III interferon family, IFN-λ4 , [3] It seems that ss469415590 has a stronger correlation with a positive outcome of pegIFN- α /RBV treatment than rs12979860 and rs8099917. Studies have found that individuals with chronic hepatitis C who express IFN- λ 4 before treatment have higher hepatic expression of ISGs but poorer ISG response to pegIFN- α /RBV treatment. Like the other members of the type III interferon family IFN- λ 4 induces STAT1 and STAT2 phosphorylation, and activate the transcription of ISGs. The exact signaling receptor of IFN- λ 4 has not been identified but based on the protein sequence it is expected to signal via IFN- λ R1. Whether it also uses IL-10R2 like the other type III interferons remains to be determined. Likewise the correlation between IFN- λ 4 expression and HCV is still not understood. IFN- λ 4 seems to be poorly exported from human cells possibly because of a very week signal peptide. We have produced, refolded and purified recombinant IFN- λ 4 in Escherichia coli . The protein is capable of inducing ISGs and has antiviral activity comparable to IFN- λ 3. Using this protein we have investigated the receptor complex utilized by IFN- λ 4. We have furthermore explored the importance of the signal peptide for the poor export of IFN- λ 4 from human cells. 1. Ge, D., et al., Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance . Nature, 2009. 461 (7262): p. 399–401, 2. Thomas, D.L., et al., Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature, 2009. 461 (7265): p. 798–801, 3. Prokunina-Olsson, L., et al., A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet, 2013. 45 (2): p. 164–71.