CRABP1 and 2 differentially regulate HCV infection via modulation of lipid droplet abundance.

Abstract

Abstract Vitamin A is an essential nutritional constituent that governs a broad spectrum of cell biology through the activation of its nuclear receptor complexes. The active metabolite of vitamin A, all-trans retinoic acid (ATRA), binds to the chaperone molecule, cytoplasmic retinoic acid binding protein (CRABP) 1 or 2 to regulate its signaling pathways. Given the extremely high homology, CRABP1 and 2 have been predicted to play a redundant role. However, a few studies by others suggested that CRABP1 and 2 might differentially regulate the cellular response to ATRA. Although the antiviral effect of ATRA is well recognized, the roles of CRABPs in the regulation of viral pathogens have never been studied. In this study, we employed hepatitis C virus (HCV) as a study model to assess the importance of CRABPs. Of great interest, CRABP1 expression enhanced HCV infection while CRABP2 expression resulted in the suppression of HCV lifecycle. Our follow up studies collectively indicated that CRABPs regulate the efficiency of HCV infection through the modulation of lipid droplet (LD) abundance wherein HCV establishes the replicase complex. The transcriptome analysis revealed that CRABP1 expression downregulated the genes regulated by ATRA and is associated with the expression of genes involved in the steatosis of the liver. In contrast, CRABP2 expression augmented ATRA response, resulting in the inhibition of LD accumulation. Moreover, the chemical inhibition of the CRABP1 and 2 pathways resulted in the abrogation of their pro- and antiviral effect, respectively. In conclusion, our study revealed a novel link between the cellular response to the micronutrients and its influence on the viral infectious disease.