Molecular mechanism of signal perception and integration by the innate immune sensor retinoic acid inducible gene-I (RIG-I).
Authors: Binder M, Eberle F, Seitz S, Mücke N, Hüber CM, Kiani N, Kaderali L, Lohmann V, Dalpke A, Bartenschlager R.
CellNetworks People: Bartenschlager Ralf, Kaderali Lars, Lohmann Volker
Journal: J Biol Chem. 2011 Aug 5;286(31):27278-87

IG-I is a major innate immune sensor for viral infection, triggering an interferon-mediated antiviral response upon cytosolic detection of viral RNA. Double-strandedness and 5'-terminal triphosphates were identified as motifs required to elicit optimal immunological signaling. However, very little is known about the response dynamics of the RIG-I pathway, which is crucial for the cell's ability to react to diverse classes of viral RNA, while maintaining self-tolerance. In the present study, we addressed the molecular mechanism of RIG-I signal detection and its translation into pathway activation. By employing highly quantitative methods, we could establish the length of the double-stranded RNA (dsRNA) to be the most critical determinant of response strength. Size exclusion chromatography and direct visualization in scanning force microscopy suggested, that this was due to cooperative oligomerization of RIG-I along dsRNA. Initiation efficiency of this oligomerization process was critically depended on the presence of high affinity motifs, like a 5'-triphosphate. Noteworthy, for dsRNA longer than 200 bp, internal initiation could effectively compensate for a lack of terminal triphosphates. In summary, our data demonstrates a very flexible response behavior of the RIG-I pathway, in which sensing and integration of at least two distinct signals- initiation efficiency and double-strand length- allows the host cell to mount an antiviral response, that is tightly adjusted to the type of the detected signal, such as viral genomes, replication intermediates or small by-products.