Abstract:
:Retinoid (vitamin A) is an essential diet constituent that governs a broad range of biological processes. Its biologically active metabolite, all-trans 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.IMPORTANCE 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.
journal_name
J Viroljournal_title
Journal of virologyauthors
Bang BR,Li M,Tsai KN,Aoyagi H,Lee SA,Machida K,Aizaki H,Jung JU,Ou JJ,Saito Tdoi
10.1128/JVI.02302-18subject
Has Abstractpub_date
2019-04-03 00:00:00issue
8eissn
0022-538Xissn
1098-5514pii
JVI.02302-18journal_volume
93pub_type
杂志文章abstract::The purified T-antigen origin binding domain binds site specifically to site II, the central region of the simian virus 40 core origin. However, in the context of full-length T antigen, the origin binding domain interacts poorly with DNA molecules containing just site II. Here we investigate the contributions of addit...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.78.6.2921-2934.2004
更新日期:2004-03-01 00:00:00
abstract::NS5A of the hepatitis C virus (HCV) is a highly phosphorylated protein involved in resistance against interferon and required most likely for replication of the viral genome. Phosphorylation of this protein is mediated by a cellular kinase(s) generating multiple proteins with different electrophoretic mobilities. In t...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.73.9.7138-7146.1999
更新日期:1999-09-01 00:00:00
abstract::The temporal sequence of coronavirus plus-strand and minus-strand RNA synthesis was determined in 17CL1 cells infected with the A59 strain of mouse hepatitis virus (MHV). MHV-induced fusion was prevented by keeping the pH of the medium below pH 6.8. This had no effect on the MHV replication cycle, but gave 5- to 10-fo...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.57.1.328-334.1986
更新日期:1986-01-01 00:00:00
abstract::The enhancer of human papillomavirus type 16 (HPV-16) is considered to be specific for epithelial cells, in particular for cervical carcinoma-derived cell lines. We reexamined this hypothesis with the complete enhancer as well as nonoverlapping subclones and found all clones to be active in epithelial cell lines deriv...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.65.11.5933-5943.1991
更新日期:1991-11-01 00:00:00
abstract::Five human recombinant Fab fragments (Fabs) specific for measles virus (MV) proteins were isolated from three antibody phage display libraries generated from RNAs derived from bone marrow or splenic lymphocytes from three MV-immune individuals. All Fabs reacted in an enzyme-linked immunosorbent assay with MV antigens....
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.76.1.251-258.2002
更新日期:2002-01-01 00:00:00
abstract::The 104-S monoclonal antibody immunoprecipitated from herpes simplex virus type 2 (HSV-2)-infected cell extracts the 75,000-molecular-weight glycoprotein gF and its 65,000-molecular-weight precursor (pgF). The precursor pgF was sensitive to endoglycosidase H digestion, indicating the presence of high mannose-type olig...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.47.1.185-192.1983
更新日期:1983-07-01 00:00:00
abstract::Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) is known to take an endosomal pathway for cell entry; however, it is thought to enter directly from the cell surface when a receptor-bound virion spike (S) protein is affected by trypsin, which induces cleavage of the S protein and activates its fusion po...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.01412-08
更新日期:2008-12-01 00:00:00
abstract::Mitochondria are important for the viral life cycle, mainly by providing the energy required for viral replication and assembly. A highly complex interaction with mitochondria is exerted by rubella virus (RV), which includes an increase in the mitochondrial membrane potential as a general marker for mitochondrial acti...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00533-13
更新日期:2013-08-01 00:00:00
abstract::Type III interferons ([IFNs] IFN-lambda and interleukin-28 and -29 [IL-28/29]) are recently recognized cytokines with innate antiviral effects similar to those of type I IFNs (IFN-alpha/beta). Like IFN-alpha/beta, IFN-lambda-expression can be induced by viruses, and it is believed that type I and III IFNs are regulate...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00717-10
更新日期:2010-09-01 00:00:00
abstract::In cell-free systems, 2-5A [ppp(A2'p)nA, n = 2 to greater than or equal to 4] activates a latent endoribonuclease, the 2-5A-dependent RNase, which cleaves rRNA in intact ribosomes into discrete and characteristic products (D. H. Wreschner et al., Nucleic Acids Res. 9:1571-1581, 1981). Here we present Northern blots wh...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.46.3.1051-1055.1983
更新日期:1983-06-01 00:00:00
abstract::A monoclonal antibody, MAb vpg15, inhibits feline immunodeficiency virus (FIV) infection in tissue culture. The antibody is directed to a determinant of the feline cell surface marker, CD9, implying that CD9 may serve as a viral receptor or coreceptor in this system. In cells expressing CD9, MAb vpg15 markedly delayed...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.8.5742-5749.1997
更新日期:1997-08-01 00:00:00
abstract::The current studies demonstrate complex and seemingly contradictory effects by gamma interferon (IFN-gamma) on Friend virus (FV) infection. Both temporal and tissue-specific effects were observed. During the first week of infection, IFN-gamma-deficiency caused increased levels of FV infection in multiple tissues. Surp...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.76.5.2225-2232.2002
更新日期:2002-03-01 00:00:00
abstract::Bats are the second largest group of mammals on earth and act as reservoirs of many emerging viruses. In this study, a novel bat adenovirus (AdV) (BtAdV-TJM) was isolated from bat fecal samples by using a bat primary kidney cell line. Infection studies indicated that most animal and human cell lines are susceptible to...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02497-09
更新日期:2010-04-01 00:00:00
abstract::Regulation of immediate-early gene expression in human cytomegalovirus is subject to complex controls. The major immediate-early (mIE) gene is regulated by both positive and negative regulatory signals, including autoregulation mediated by a cis-repressive sequence. A second immediate-early gene, the US3 gene, is tran...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.69.9.5362-5367.1995
更新日期:1995-09-01 00:00:00
abstract::YY1 is a zinc finger transcription factor which acts as either a repressor or an activator dependent on the promoter context. YY1 is a potent activator of the genuine human papillomavirus type 18 (HPV-18) upstream regulatory region (URR) in HeLa cells, which are known for high-level expression of the HPV-18 early gene...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.69.1.1-12.1995
更新日期:1995-01-01 00:00:00
abstract::Multimerization of the Hantaan virus nucleocapsid protein (NP) in Hantaan virus-infected Vero E6 cells was observed in a competitive enzyme-linked immunosorbent assay (ELISA). Recombinant and truncated NPs of Hantaan, Seoul, and Dobrava viruses lacking the N-terminal 49 amino acids were also detected as multimers. Alt...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.77.2.943-952.2003
更新日期:2003-01-01 00:00:00
abstract::Of the numerous endogenous retroviral elements that are present in the human genome, the abundant HERV-K family is distinct because several members are transcriptionally active and coding for biologically active proteins. A detailed phylogeny of the HERV-K family based on the partial sequence of the reverse transcript...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.73.3.2365-2375.1999
更新日期:1999-03-01 00:00:00
abstract::We have detected a mouse mammary tumor virus (MMTV)-specific 1.7-kilobase (kb) polyadenylated RNA in mammary glands of several mouse strains. In BALB/c mice, it is the only MMTV-specific RNA species present. C3H and GR mammary glands and tumors contain, in addition, 3.8- and 7.8-kb MMTV RNAs. Nuclease S1 analysis was ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.46.2.362-370.1983
更新日期:1983-05-01 00:00:00
abstract::Cell-free translation of separated Sendai virus mRNA species identified the message for polypeptide M and suggested the identity of the message for polypeptide NP. ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.28.1.411-414.1978
更新日期:1978-10-01 00:00:00
abstract::Heterologous viral infections have been shown to impact the preexisting memory CD8(+)-T-cell repertoire. Bacterial superantigens are products of common human pathogenic bacteria, including staphylococci and streptococci, that are potent T-cell-stimulatory molecules. In this report, we show that exposure to staphylococ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.76.13.6852-6856.2002
更新日期:2002-07-01 00:00:00
abstract::Several C/EBP binding sites within the Rous sarcoma virus (RSV) long terminal repeat (LTR) and gag enhancers were mutated, and the effect of these mutations on viral gene expression was assessed. Minimal site-specific mutations in each of three adjacent C/EBP binding sites in the LTR reduced steady-state viral RNA lev...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.67.5.2862-2870.1993
更新日期:1993-05-01 00:00:00
abstract::A major challenge for the development of an effective HIV vaccine is to elicit neutralizing antibodies against a broad array of primary isolates. Monomeric gp120-based vaccine approaches have not been successful in inducing this type of response, prompting a number of approaches designed to recreate the native glycopr...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.79.23.14804-14814.2005
更新日期:2005-12-01 00:00:00
abstract::Heterozygous replicative form molecules of bacteriophage phiX174 deoxyribonucleic acid (DNA) have been constructed in vitro. These are composed of viral strands extracted from purified preparations of phage bearing ts mutations and complementary strands of either half length or full length synthesized with purified DN...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.7.5.603-611.1971
更新日期:1971-05-01 00:00:00
abstract::A panel of seven monoclonal antibodies against the relatively conserved CD4-binding domain on human immunodeficiency virus type 1 (HIV-1) gp120 was generated by immunizing mice with purified gp120. These monoclonal antibodies reacted specifically with gp120 in an enzyme-linked immunosorbent assay and Western blots (im...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.63.9.3579-3585.1989
更新日期:1989-09-01 00:00:00
abstract::The herpes simplex virus type 1 (HSV-1) tegument is the least understood component of the virion, and the mechanism of tegument assembly and incorporation into virions during viral egress has not yet been elucidated. In the present study, the addition of tegument proteins (VP13/14, VP16, VP22, and US9) and envelope gl...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.76.19.9934-9951.2002
更新日期:2002-10-01 00:00:00
abstract::The functions of the two rotavirus glycoproteins were investigated by using tunicamycin and a variant of SA11 rotavirus having nonglycosylated VP7. Results showed that glycosylation of VP7 is not required for normal viral morphogenesis and infectivity and suggested that the nonstructural glycoprotein is involved in as...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.46.1.270-274.1983
更新日期:1983-04-01 00:00:00
abstract::The early steps of the intracellular trafficking of human papillomavirus type 16 (HPV-16), -31, and -58 pseudovirions were studied by investigating the effects of drugs acting at defined points of endocytosis pathways on virus-like particle-mediated pseudoinfection by overexpression of a dominant-negative form of the ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.77.6.3846-3850.2003
更新日期:2003-03-01 00:00:00
abstract::The complete nucleotide sequences of the vesicular stomatitis virus mRNA's encoding the glycoprotein (G) and the matrix protein (M) have been determined from cDNA clones that contain the complete coding sequences from each mRNA. The G protein mRNA is 1,665 nucleotides long, excluding polyadenylic acid, and encodes a p...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.39.2.519-528.1981
更新日期:1981-08-01 00:00:00
abstract::The V20 cultivar of Nicotiana tabacum was shown previously to exhibit a strain-specific restriction of long-distance movement of tobacco etch potyvirus (TEV). In V20, both TEV-HAT and TEV-Oxnard strains are capable of genome amplification and cell-to-cell movement, but only TEV-Oxnard is capable of systemic infection ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.11.8624-8631.1997
更新日期:1997-11-01 00:00:00
abstract::High concentrations of either trypsin or chymotrypsin caused nearly complete cleavage of capsid protein VP2 of hepatitis A virus but did not significantly reduce the infectivity, thermostability, or antigenicity of the virus. Chymotrypsin also had a lesser effect on VP1. These findings indicate the presence of a prote...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.65.10.5636-5640.1991
更新日期:1991-10-01 00:00:00