FIG 2.

Spatiotemporal RIG-I activation by the IAV panhandle RNA signatures during infection. (1) Incoming vRNPs and DI RNAs (presumably encapsidated in DI RNPs) directly activate cytoplasmic RIG-I (cRIG-I); (2) during genome replication, mini viral RNAs (mvRNA) and DI RNAs (naked or RNPs) synthesized by an erroneous viral polymerase are exported into the cytoplasm whereby activating cRIG-I; (3 and 4) small viral RNAs (svRNA) and aberrant viral RNAs (abvRNA) anneal to the full-length template cRNA (3) or vRNA (4) to form fully or partially complementary (panhandle-like) RNA duplexes activating nRIG-I; (5) nRIG-I recognizes the panhandle structure within progeny vRNPs and forms oligomers with activated cRIG-I that cross the nuclear membrane, thereby activating MAVS; (6) at the late stage of infection, activated nRIG-I directly engages MAVS localized on perinuclear mitochondria owing to the increased nuclear membrane permeability; (7) exported vRNPs and DI RNPs activate cRIG-I prior to genome packaging; (8) nuclear-to-cytoplasmic relocalization of 5S rRNA pseudogene 141 (RNA5SP141) activates cRIG-I upon IAV-induced shutoff of RNA binding protein synthesis.