title: Zinc-finger antiviral protein mediates retinoic acid inducible gene I-like receptor-independent antiviral response to murine leukemia virus.
abstract: When host cells are infected by an RNA virus, pattern-recognition receptors (PRRs) recognize the viral RNA and induce the antiviral innate immunity. Toll-like receptor 7 (TLR7) detects the genomic RNA of incoming murine leukemia virus (MLV) in endosomes and mediates the antiviral response. However, the RNA-sensing PRR that recognizes the MLV in the cytosol is not fully understood. Here, we definitively demonstrate that zinc-finger antiviral protein (ZAP) acts as a cytosolic RNA sensor, inducing the degradation of the MLV transcripts by the exosome, an RNA degradation system, on RNA granules. Although the retinoic acid inducible gene I (RIG-I)-like receptors (RLRs) RIG-I and melanoma differentiation-associated protein 5 detect various RNA viruses in the cytosol and induce the type I IFN-dependent antiviral response, RLR loss does not alter the replication efficiency of MLV. In sharp contrast, the loss of ZAP greatly enhances the replication efficiency of MLV. ZAP localizes to RNA granules, where the processing-body and stress-granule proteins assemble. ZAP induces the recruitment of the MLV transcripts and exosome components to the RNA granules. The CCCH-type zinc-finger domains of ZAP, which are RNA-binding motifs, mediate its localization to RNA granules and MLV transcripts degradation by the exosome. Although ZAP was known as a regulator of RIG-I signaling in a human cell line, ZAP deficiency does not affect the RIG-I-dependent production of type I IFN in mouse cells. Thus, ZAP is a unique member of the cytosolic RNA-sensing PRR family that targets and eliminates intracellular RNA viruses independently of TLR and RLR family members.
authors.affiliation: Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
authors.forename: Hanna
authors.initials: H
authors.lastname: Lee
authors.forename: Jun
authors.initials: J
authors.lastname: Komano
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Saitoh
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamaoka
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kozaki
authors.forename: Takuma
authors.initials: T
authors.lastname: Misawa
authors.forename: Michihiro
authors.initials: M
authors.lastname: Takahama
authors.forename: Takashi
authors.initials: T
authors.lastname: Satoh
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Matsuura
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Saitoh
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000502:physiology*; D009052:Leukemia Virus, Murine / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D014779:Virus Replication / Q000187:drug effects; D016335:Zinc Fingers
chemical_list: C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases
keywords: ZC3HAV1; host defense; retrovirus