A Nonself RNA Pattern: Tri-p to Panhandle
2009; Cell Press; Volume: 31; Issue: 1 Linguagem: Inglês
10.1016/j.immuni.2009.06.014
ISSN1097-4180
Autores Tópico(s)RNA regulation and disease
ResumoIn this issue of Immunity, Schlee et al., 2009Schlee M. Roth A. Hornung V. Hagmann C.A. Wimmenauer V. Barchet W. Coch C. Janke M. Mihailovic A. Wardle G. et al.Immunity. 2009; 31 (this issue): 25-34Abstract Full Text Full Text PDF PubMed Scopus (521) Google Scholar defines key RNA structures recognized by a cellular viral sensor, RIG-I. This and another recent report by Schmidt et al., 2009Schmidt A. Schwerd T. Hamm W. Hellmuth J.C. Cui S. Wenzel M. Hoffmann F. Michallet M.C. Besch R. Hopfner K.P. et al.Proc. Natl. Acad. Sci. USA. 2009; https://doi.org/10.1073/pnas.0900971106Crossref Scopus (299) Google Scholar provide new insights into the mechanism of antiviral innate immunity. In this issue of Immunity, Schlee et al., 2009Schlee M. Roth A. Hornung V. Hagmann C.A. Wimmenauer V. Barchet W. Coch C. Janke M. Mihailovic A. Wardle G. et al.Immunity. 2009; 31 (this issue): 25-34Abstract Full Text Full Text PDF PubMed Scopus (521) Google Scholar defines key RNA structures recognized by a cellular viral sensor, RIG-I. This and another recent report by Schmidt et al., 2009Schmidt A. Schwerd T. Hamm W. Hellmuth J.C. Cui S. Wenzel M. Hoffmann F. Michallet M.C. Besch R. Hopfner K.P. et al.Proc. Natl. Acad. Sci. USA. 2009; https://doi.org/10.1073/pnas.0900971106Crossref Scopus (299) Google Scholar provide new insights into the mechanism of antiviral innate immunity. When we get infected by viruses, our cells detect their replication and initiate an antiviral response program that includes production of type I interferon (IFN-I) within hours of infection. Although some Toll-like receptors (TLR3, TLR7, and TLR8) detect viral RNA released from the infected cells, RIG-I and related RNA helicases, MDA5 and LGP2, recognize viral RNA in the cytoplasm (Yoneyama and Fujita, 2009Yoneyama M. Fujita T. Immunol. Rev. 2009; 227: 54-65Crossref PubMed Scopus (432) Google Scholar). With gene-deleted mice and cells, it was demonstrated that RIG-I participates in the detection of a variety of viruses including influenza A, Sendai, Newcastle disease, Vesicular stomatitis, and Japanese encephalitis viruses. In contrast, the picornaviridae family of virus is selectively detected by MDA5. Some viruses including West Nile virus are detected by both RIG-I and MDA5. The differential recognition by these sensors is suggested to arise from distinct specificity for RNA structures. A classical nonself RNA is double-stranded (ds) RNA, which is not detectable in uninfected cells, consistent with the lack of an RNA-dependent RNA polymerase in mammalian cells. A systemic investigation revealed that RIG-I and MDA5 preferentially recognize short and long dsRNA, respectively (Kato et al., 2008Kato H. Takeuchi O. Mikamo-Satoh E. Hirai R. Kawai T. Matsushita K. Hiiragi A. Dermody T.S. Fujita T. Akira S. J. Exp. Med. 2008; 205: 1601-1610Crossref PubMed Scopus (1039) Google Scholar). However, use of a dsRNA monoclonal antibody as a probe showed that some viruses, including influenza virus A, do not produce detectable amounts of dsRNA in infected cells, suggesting another type of RNA pattern that is recognized by RIG-I (Pichlmair et al., 2006Pichlmair A. Schulz O. Tan C.P. Naslund T.I. Liljestrom P. Weber F. Reis e Sousa C. Science. 2006; 314: 997-1001Crossref PubMed Scopus (1553) Google Scholar). Two reports revealed that viral RNA with 5′ triphosphate (5′ tri-p) is a crucial determinant for nonself RNA recognition by RIG-I (Hornung et al., 2006Hornung V. Ellegast J. Kim S. Brzozka K. Jung A. Kato H. Poeck H. Akira S. Conzelmann K.K. Schlee M. et al.Science. 2006; 314: 994-997Crossref PubMed Scopus (1729) Google Scholar, Pichlmair et al., 2006Pichlmair A. Schulz O. Tan C.P. Naslund T.I. Liljestrom P. Weber F. Reis e Sousa C. Science. 2006; 314: 997-1001Crossref PubMed Scopus (1553) Google Scholar). Although cellular RNA transcribed in the nucleus fails to activate the IFN-1 pathway because it undergoes removal of 5′ tri-p prior to transport to the cytoplasm, RNA polymer containing 5′ tri-p, produced by in vitro transcription with phage RNA polymerase, efficiently activates IFN-I production in RNA-transfected cells. 5′ tri-p is necessary because its removal by phosphatase rendered the RNA refractory to detection by RIG-I. However, Schlee et al., 2009Schlee M. Roth A. Hornung V. Hagmann C.A. Wimmenauer V. Barchet W. Coch C. Janke M. Mihailovic A. Wardle G. et al.Immunity. 2009; 31 (this issue): 25-34Abstract Full Text Full Text PDF PubMed Scopus (521) Google Scholar, in this issue of Immunity, and a separate report by Schmidt et al., 2009Schmidt A. Schwerd T. Hamm W. Hellmuth J.C. Cui S. Wenzel M. Hoffmann F. Michallet M.C. Besch R. Hopfner K.P. et al.Proc. Natl. Acad. Sci. USA. 2009; https://doi.org/10.1073/pnas.0900971106Crossref Scopus (299) Google Scholar discovered that 5′ tri-p alone is not sufficient for downstream signaling. They found that chemically synthesized 5′ tri-p RNA without use of the phage polymerase is unable to activate IFN-I production. In vitro RNA transcripts often contain double-stranded structures as a result of a "copy back" mechanism from the 3′ end. Schlee et al., 2009Schlee M. Roth A. Hornung V. Hagmann C.A. Wimmenauer V. Barchet W. Coch C. Janke M. Mihailovic A. Wardle G. et al.Immunity. 2009; 31 (this issue): 25-34Abstract Full Text Full Text PDF PubMed Scopus (521) Google Scholar made a through investigation on short dsRNA ( 20 bp. The genome of many negative-strand viruses, including influenza A, Rabies, and Measles viruses, contain partial complementary sequences at 5′ and 3′ regions. These regions are critical for viral replication, transcription, and translation, presumably by forming base pairs, a structure also known as the panhandle. Because the presumed panhandle regions of the viral genomes contain blunt-ended 5′ tri-p structure, these might serve as strong agonists for RIG-I. Indeed, Schlee et al., 2009Schlee M. Roth A. Hornung V. Hagmann C.A. Wimmenauer V. Barchet W. Coch C. Janke M. Mihailovic A. Wardle G. et al.Immunity. 2009; 31 (this issue): 25-34Abstract Full Text Full Text PDF PubMed Scopus (521) Google Scholar synthesized a Rabies viral panhandle (without a pan) and demonstrated that it can activate RIG-I. RIG-I is composed of three main domains. The ATPase-RNA helicase domain of RIG-I is the largest portion of RIG-I and is implicated for conformational change upon activation. The C-terminal region is responsible for RNA recognition (Cui et al., 2008Cui S. Eisenacher K. Kirchhofer A. Brzozka K. Lammens A. Lammens K. Fujita T. Conzelmann K.K. Krug A. Hopfner K.P. Mol. Cell. 2008; 29: 169-179Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar, Takahasi et al., 2008Takahasi K. Yoneyama M. Nishihori T. Hirai R. Kumeta H. Narita R. Gale Jr., M. Inagaki F. Fujita T. Mol. Cell. 2008; 29: 428-440Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar). The N-terminal domain containing tandem repeat of caspase activation and recruitment domain (CARD) is responsible for relaying the signal to downstream effectors (Yoneyama and Fujita, 2009Yoneyama M. Fujita T. Immunol. Rev. 2009; 227: 54-65Crossref PubMed Scopus (432) Google Scholar). It has been proposed that in a repressed state, CARD is masked by the action of the C-terminal domain; however, upon RNA binding, conformational change is induced, thereby exposing CARD (Takahasi et al., 2008Takahasi K. Yoneyama M. Nishihori T. Hirai R. Kumeta H. Narita R. Gale Jr., M. Inagaki F. Fujita T. Mol. Cell. 2008; 29: 428-440Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar). Schmidt et al., 2009Schmidt A. Schwerd T. Hamm W. Hellmuth J.C. Cui S. Wenzel M. Hoffmann F. Michallet M.C. Besch R. Hopfner K.P. et al.Proc. Natl. Acad. Sci. USA. 2009; https://doi.org/10.1073/pnas.0900971106Crossref Scopus (299) Google Scholar demonstrated that both 5′ tri-p and short dsRNA moiety, respectively, form a complex with RIG-I. Furthermore, a biologically active RNA molecule with both of these structures induces a RIG-I dimer. Taken together, these results suggest a new model (Figure 1) in which 5′ tri-p and double-stranded structures present in one RNA molecule bridge two RIG-I molecules to facilitate RIG-I dimer (oligomer) formation, which has been observed in virus-infected cells (Saito et al., 2007Saito T. Hirai R. Loo Y.M. Owen D. Johnson C.L. Sinha S.C. Akira S. Fujita T. Gale Jr., M. Proc. Natl. Acad. Sci. USA. 2007; 104: 582-587Crossref PubMed Scopus (530) Google Scholar). However, there are several issues to be resolved before finalizing this model, particularly, the mechanism of recognition of the two nonself signatures by domains of RIG-I should be elucidated. Schlee et al., 2009Schlee M. Roth A. Hornung V. Hagmann C.A. Wimmenauer V. Barchet W. Coch C. Janke M. Mihailovic A. Wardle G. et al.Immunity. 2009; 31 (this issue): 25-34Abstract Full Text Full Text PDF PubMed Scopus (521) Google Scholar and Schmidt et al., 2009Schmidt A. Schwerd T. Hamm W. Hellmuth J.C. Cui S. Wenzel M. Hoffmann F. Michallet M.C. Besch R. Hopfner K.P. et al.Proc. Natl. Acad. Sci. USA. 2009; https://doi.org/10.1073/pnas.0900971106Crossref Scopus (299) Google Scholar uncovered that 5′ tri-p and panhandle structures of viral RNA are crucial for RIG-I activation to initiate an antiviral response program. The dual detection facilitates highly specific recognition and avoids unnecessary activation of the IFN system, which is sometimes toxic to normal cellular function. Recognition of 5′ Triphosphate by RIG-I Helicase Requires Short Blunt Double-Stranded RNA as Contained in Panhandle of Negative-Strand VirusSchlee et al.ImmunityJuly 2, 2009In BriefAntiviral immunity is triggered by immunorecognition of viral nucleic acids. The cytosolic helicase RIG-I is a key sensor of viral infections and is activated by RNA containing a triphosphate at the 5′ end. The exact structure of RNA activating RIG-I remains controversial. Here, we established a chemical approach for 5′ triphosphate oligoribonucleotide synthesis and found that synthetic single-stranded 5′ triphosphate oligoribonucleotides were unable to bind and activate RIG-I. Conversely, the addition of the synthetic complementary strand resulted in optimal binding and activation of RIG-I. Full-Text PDF Open Archive
Referência(s)