ID: 191: Comparing the stability and activity of recombinant IFNλ3 and IFNλ4
Hepatitis C virus (HCV) infection is one of the major causes of liver cancer worldwide and every year 3–4 million people become infected. Whereas some infected people eradicate the virus spontaneously, almost 85% do not and instead develop a chronic infection. Recently, it was shown that people with a functional IFNL4 gene have a lower chance of clearing the virus spontaneously or in response to treatment than people with a non-functional IFNL4 gene. Why it is a disadvantage to have a functional IFNL4 gene during HCV infection is currently not known although a causal relationship between the activity of the IFN λ 4 protein and poor HCV clearance has been demonstrated. IFN λ 4 belongs to the type III IFNs together with IFN λ 1, -2, and -3. However, it differs from the others not only by its low sequence similarity but also by its impaired secretion. This impairment is not due to a weak signal peptide, as swapping the signal peptides between IFN λ 3 and -4 had no effect on secretion. When we purified IFN λ 3 and -4, we found that IFN λ 4 is far more difficult to refold in vitro than IFN λ 3 suggesting that the poor secretion of IFN λ 4 could be due to an inherent problem of folding the protein. Because such a problem could also mean that IFN λ 4 could be far unstable than the other type III IFNs, we decided to compare the stability of recombinant IFN λ 3 and IFN λ 4. Our results demonstrate that IFN λ 4 like IFN λ 3 is surprisingly stable once it has folded properly.