The unfolded protein response contributes to antiproliferative and proapoptotic effects of IFN-λ4 in human hepatic cells

Abstract

Abstract IFN-λ4 is a type-III interferon with strong clinical significance in humans. Only individuals who carry the ΔG allele of a genetic variant rs368234815-TT/ΔG are genetically able to produce IFN-λ4 protein. Carriers of the ΔG allele have impaired ability to clear hepatitis C virus (HCV) infection, however the mechanisms are not fully understood. Here, we used RNA-seq to evaluate the effects of IFN-λ4 and IFN-λ3 expression in inducible hepatic cell lines (HepG2) with and without the receptor (IFNLR) required for signaling of both interferons. Pathway analysis showed that despite being poorly secreted, IFN-λ4 expression induced a stronger ISG response compared to IFN-λ3. IFN-λ4 expression was also associated with reduced proliferation and increased expression of genes involved in the unfolded protein response (UPR). Subcellular localization analysis revealed that IFN-λ4 was accumulated in the Golgi and lysosomes, suggesting it is misfolded and targeted for elimination. Furthermore, intrinsic but not extrinsic expression of IFN-λ4 inhibited cell proliferation via cell cycle arrest leading to apoptosis; both indicative of UPR outcomes. In conclusion, our results show that in addition to inducing ISGs, IFN-λ4 expression induces UPR, contributing to inhibition of cell proliferation. This could have important consequences for conditions such as HCV and fibrosis, where IFN-λ4 expression has been implicated.