Structural basis of innate immune recognition of viral RNA

Viral RNA is recognized by innate immune receptors from two different families. In endolysosomal compartments, Toll‐like receptors (TLRs) 3, 7 and 8 recognize either double‐stranded RNA (dsRNA) or single‐stranded RNA. In the cytoplasm, viral genomic RNA or transcriptional intermediates are recognized by DExD/H‐box helicases RIG‐I and MDA5. Recent structural studies of these RNA sensors have provided atomic‐level insight into the recognition mechanism of viral RNA. TLR3 dimerizes around a straight 45‐bp stretch of dsRNA, explaining the length requirement of at least 40 bp for dsRNA recognition. RIG‐I recognizes blunt ends of dsRNA with 5′‐triphosphate caps. Ligand binding releases RIG‐I from a closed autoinhibited state, exposing the CARD signalling domains. MDA5 recognizes long dsRNA by cooperatively assembling into helical filaments. RNA recognition by RIG‐I and MDA5 triggers assembly of their common downstream signalling adaptor MAVS from its inactive monomeric form into its active polymeric form. While RIG‐I and MDA5 appear to activate MAVS via distinct oligomerization mechanisms, a common paradigm is emerging in innate immunity for signal transduction by oligomerization‐dependent signalling platforms. Many open questions remain including the role of proteolytic activation in RNA recognition by TLR3 and how unanchored ubiquitin chains contribute to RNA recognition by RIG‐I and MDA5.