Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Bioinformatics Service, Norris Medical Library, University of Southern California, Los Angeles, California, USA.
J Virol. 2019 Apr 3;93(8). doi: 10.1128/JVI.02302-18. Print 2019 Apr 15.
Retinoid (vitamin A) is an essential diet constituent that governs a broad range of biological processes. Its biologically active metabolite, all- retinoic acid (ATRA), exhibits a potent antiviral property by enhancing both innate and adaptive antiviral immunity against a variety of viral pathogens, such as, but not limited to, HIV, respiratory syncytial virus (RSV), herpes simplex virus (HSV), and measles. Even though the hepatocyte is highly enriched with retinoid and its metabolite ATRA, it supports the establishment of efficient hepatitis C virus (HCV) replication. Here, we demonstrate the hepatocyte-specific cell-intrinsic mechanism by which ATRA exerts either a proviral or antiviral effect, depending on how it engages cellular retinoic acid binding proteins (CRABPs). We found that the engagement of CRABP1 by ATRA potently supported viral infection by promoting the accumulation of lipid droplets (LDs), which robustly enhanced the formation of a replication complex on the LD-associated endoplasmic reticulum (ER) membrane. In contrast, ATRA binding to CRABP2 potently inhibited HCV via suppression of LD accumulation. However, this antiviral effect of CRABP2 was abrogated due to the functional and quantitative predominance of CRABP1 in the hepatocytes. In summary, our study demonstrates that CRABPs serve as an on-off switch that modulates the efficiency of the HCV life cycle and elucidates how HCV evades the antiviral properties of ATRA via the exploitation of CRABP1 functionality. ATRA, a biologically active metabolite of vitamin A, exerts pleiotropic biological effects, including the activation of both innate and adaptive immunity, thereby serving as a potent antimicrobial compound against numerous viral pathogens. Despite the enrichment of hepatocytes with vitamin A, HCV still establishes an efficient viral life cycle. Here, we discovered that the hepatocellular response to ATRA creates either a proviral or an antiviral environment depending on its engagement with CRABP1 or -2, respectively. CRABP1 supports the robust replication of HCV, while CRABP2 potently inhibits the efficiency of viral replication. Our biochemical, genetic, and microscopic analyses reveal that the pro- and antiviral effects of CRABPs are mediated by modulation of LD abundance, where HCV establishes the platform for viral replication and assembly on the LD-associated ER membrane. This study uncovered a cell-intrinsic mechanism by which HCV exploits the proviral function of CRABP1 to establish an efficient viral life cycle.
视黄醇（维生素 A）是一种重要的饮食成分，可调控广泛的生物过程。其生物活性代谢物全反式视黄酸（ATRA）通过增强先天和适应性抗病毒免疫，对多种病毒病原体（如 HIV、呼吸道合胞病毒（RSV）、单纯疱疹病毒（HSV）和麻疹）具有强大的抗病毒特性。尽管肝细胞富含视黄醇及其代谢物 ATRA，但它支持丙型肝炎病毒（HCV）的高效复制。在这里，我们展示了 ATRA 通过细胞内固有机制发挥促病毒或抗病毒作用的机制，具体取决于它与细胞视黄酸结合蛋白（CRABP）的结合方式。我们发现，ATRA 与 CRABP1 的结合通过促进脂滴（LDs）的积累，有力地增强了 LD 相关内质网上复制复合物的形成，从而强力支持病毒感染。相比之下，ATRA 与 CRABP2 的结合通过抑制 LD 积累来强力抑制 HCV。然而，由于 CRABP1 在肝细胞中的功能和数量优势，CRABP2 的这种抗病毒作用被削弱。总之，我们的研究表明，CRABPs 作为一个开/关开关，调节 HCV 生命周期的效率，并阐明 HCV 如何通过利用 CRABP1 的功能来逃避 ATRA 的抗病毒特性。ATRA 是维生素 A 的生物活性代谢物，具有多种生物学效应，包括先天免疫和适应性免疫的激活，因此是针对多种病毒病原体的有效抗菌化合物。尽管肝细胞富含维生素 A，但 HCV 仍建立了高效的病毒生命周期。在这里，我们发现肝细胞对 ATRA 的反应根据其与 CRABP1 或 -2 的结合情况，分别创造了促病毒或抗病毒环境。CRABP1 支持 HCV 的强烈复制，而 CRABP2 强力抑制病毒复制的效率。我们的生化、遗传和显微镜分析揭示了 CRABP 的促病毒和抗病毒作用是通过调节 LD 丰度来介导的，HCV 在 LD 相关内质网膜上建立了病毒复制和组装的平台。这项研究揭示了一种细胞内固有机制，通过该机制，HCV 利用 CRABP1 的促病毒功能来建立高效的病毒生命周期。
