Sensors for replicating viruses and innate immunity

フォーマット:

論文

責任表示:

Fujita, Takashi

言語:

英語

出版情報:

弘前大学大学院医学研究科・弘前医学会, 2007-11-29

著者名:

Fujita, Takashi  

掲載情報:

弘前医学

ISSN:

0439-1721      

巻:

59

通号:

Supplement

開始ページ:

S52

終了ページ:

S57

バージョン:

publisher

概要:

Recent studies show the involvement of cytoplasmic RNA helicase family, RIG-I, MDA5 and LGP2 inantiviral innate immune responses. RIG-I and MDA5 are primarily responsible for the detection of viral infectionand triggering activation cascade for type I interferon genes in many cell types. RIG-I consists of N-terminalCAspase Recruitment Domain (CARD) and a domain with signatures of DExD/H box helicase (helicase domain).Functional analyses revealed that the … helicase domain detects viral RNA and CARD triggers the activation ofdownstream signaling cascade, including activation of transcription factors, NF-κB, IRF-3 and IRF-7. RIG-I bindsto double stranded (ds)RNA, however it does not simply function as a binding receptor for dsRNA, since RIG-Iwith disrupted ATP binding site is incapable of signaling. A model is proposed that in the absence of dsRNA,RIG-I forms “closed” conformation and upon binding to dsRNA, it conforms into “open” structure exposing CARD.We produced recombinant RIG-I protein using Baculo virus system and purified it to homogeneity. Biochemicalproperties, including dsRNA binding activity, ATPase activity and helicase activity, of recombinant RIG-I wereinvestigated. The results suggested that RIG-I requires certain structure of ligand RNA that is specifi c to viral (ornon-self) origin. Furthermore, we found evidence that RIG-I conforms a certain structure upon binding to dsRNA inthe presence of ATP. These results were consistent with the above model for activation of RIG-I. Furthermore, weobserved that RIG-I forms oligomers in virus-infected cells and artifi cial oligomerization of RIG-I CARD mimics virusinducedsignaling, resulting in the activation of interferon and other cytokine genes. These results highlight how viralreplication in cytoplasm is detected by RIG-I helicase and switch on signal cascades for initial antiviral responses. 続きを見る

URL:

http://hdl.handle.net/10129/2216