ID: 194: Role of microRNAs in signal transduction pathways of the inflammatory cytokine Interleukin-6: Relevance for liver diseases

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 IFNk4 protein and poor HCV clearance has been demonstrated. IFNk4 belongs to the type III IFNs together with IFNk1, -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 IFNk3 and -4 had no effect on secretion. When we purified IFNk3 and -4, we found that IFNk4 is far more difficult to refold in vitro than IFNk3 suggesting that the poor secretion of IFNk4 could be due to an inherent problem of folding the protein. Because such a problem could also mean that IFNk4 could be far unstable than the other type III IFNs, we decided to compare the stability of recombinant IFNk3 and IFNk4. Our results demonstrate that IFNk4 like IFNk3 is surprisingly stable once it has folded properly.