Critical role of an antiviral stress granule containing RIG-I and PKR in viral detection and innate immunity.
Retinoic acid inducible gene I (RIG-I)-like receptors (RLRs) function as cytoplasmic sensors for viral RNA to initiate antiviral responses including type I interferon (IFN) production. It has been unclear how RIG-I encounters and senses viral RNA. To address this issue, we examined intracellular localization of RIG-I in response to viral infection using newly generated anti-RIG-I antibody. Immunohistochemical analysis revealed that RLRs localized in virus-induced granules containing stress granule (SG) markers together with viral RNA and antiviral proteins. Because of similarity in morphology and components, we termed these aggregates antiviral stress granules (avSGs). Influenza A virus (IAV) deficient in non-structural protein 1 (NS1) efficiently generated avSGs as well as IFN, however IAV encoding NS1 produced little. Inhibition of avSGs formation by removal of either the SG component or double-stranded RNA (dsRNA)-dependent protein kinase (PKR) resulted in diminished IFN production and concomitant enhancement of viral replication. Furthermore, we observed that transfection of dsRNA resulted in IFN production in an avSGs-dependent manner. These results strongly suggest that the avSG is the locus for non-self RNA sensing and the orchestration of multiple proteins is critical in the triggering of antiviral responses.
Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Koji
K
Onomoto
Michihiko
M
Jogi
Ji-Seung
JS
Yoo
Ryo
R
Narita
Shiho
S
Morimoto
Azumi
A
Takemura
Suryaprakash
S
Sambhara
Atushi
A
Kawaguchi
Suguru
S
Osari
Kyosuke
K
Nagata
Tomoh
T
Matsumiya
Hideo
H
Namiki
Mitsutoshi
M
Yoneyama
Takashi
T
Fujita
D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D002522:Chlorocebus aethiops; D003594:Cytoplasmic Granules / Q000276:immunology*; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology* / Q000378:metabolism; D005347:Fibroblasts; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007150:Immunohistochemistry; D009980:Influenza A virus / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D012367:RNA, Viral / Q000378:metabolism*; D014709:Vero Cells; D019892:eIF-2 Kinase / Q000276:immunology* / Q000378:metabolism
D000914:Antibodies, Viral; D007370:Interferon Type I; D012367:RNA, Viral; D019892:eIF-2 Kinase; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases