title: DDX3 functions in antiviral innate immunity through translational control of PACT.
abstract: It has emerged that DDX3 plays a role in antiviral innate immunity. However, the exact mechanism by which DDX3 functions in antiviral innate immunity remains to be determined. We found that the expression of the protein activator of the interferon-induced protein kinase (PACT) was regulated by DDX3 in human cells. PACT acts as a cellular activator of retinoic acid-inducible gene-I-like receptors in the sensing of viral RNAs. DDX3 facilitated the translation of PACT mRNA that may contain a structured 5' UTR. Knockdown of DDX3 decreased the viral RNA detection sensitivity of the cells. PACT partially rescued defects of interferon-β1 and chemokine (C-C motif) ligand 5/RANTES (regulated on activation normal T cell expressed and secreted) induction in DDX3-knockdown HEK293 cells. Therefore, DDX3 may participate in antiviral innate immunity, at least in part, by translational control of PACT. Moreover, we show that overexpression of the hepatitis C virus (HCV) core protein inhibited the translation of a reporter mRNA harboring the PACT 5' UTR. The HCV core protein was associated and colocalized with DDX3 in cytoplasmic stress granules, suggesting that the HCV core may abrogate the function of DDX3 by sequestering DDX3 in stress granules. The perturbation of DDX3 by viral proteins delineates a critical role for DDX3 in antiviral host defense.
authors.affiliation: Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Lai
authors.affiliation: Institute of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: H Sunny
authors.initials: HS
authors.lastname: Sun
authors.affiliation: Institute of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Shainn-Wei
authors.initials: SW
authors.lastname: Wang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Woan-Yuh
authors.initials: WY
authors.lastname: Tarn
mesh_terms: D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D014407:Tumor Cells, Cultured; D014758:Viral Core Proteins / Q000378:metabolism; D014780:Viruses / Q000276:immunology*
chemical_list: C104647:PRKRA protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases
keywords: DDX3; PACT; antiviral innate immunity; hepatitis C virus; translational control