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Review
. 2019 Apr 3;93(8):e02299-18.
doi: 10.1128/JVI.02299-18. Print 2019 Apr 15.

Cytoplasm and Beyond: Dynamic Innate Immune Sensing of Influenza A Virus by RIG-I

GuanQun Liu  1 , Yan Zhou  2
Affiliations
Review

Cytoplasm and Beyond: Dynamic Innate Immune Sensing of Influenza A Virus by RIG-I

GuanQun Liu et al. J Virol. .

Abstract

Innate immune sensing of influenza A virus (IAV) requires retinoic acid-inducible gene I (RIG-I), a fundamental cytoplasmic RNA sensor. How RIG-I's cytoplasmic localization reconciles with the nuclear replication nature of IAV is poorly understood. Recent findings provide advanced insights into the spatiotemporal RIG-I sensing of IAV and highlight the contribution of various RNA ligands to RIG-I activation. Understanding a compartment-specific RIG-I-sensing paradigm would facilitate the identification of the full spectrum of physiological RIG-I ligands produced during IAV infection.

Keywords: RIG-I; defective interfering RNA; influenza A virus; innate immunity; panhandle.

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Figures

FIG 1
FIG 1
RIG-I activation by genomic panhandle structures of IAV and other negative-strand RNA viruses. The IAV genomic promoter region adopts alternate RNA structures, such as the panhandle and corkscrew configurations. The panhandle structure can be divided into a proximal stem (5′ nucleotide positions 1 to 9 and 3′ nucleotide positions 1 to 9) and a distal stem (5′ nucleotide positions 11 to 16 and 3′ nucleotide positions 10 to 15) linked through an unpaired adenosine (5′ nucleotide position 10). The panhandle proximal stem contains two G:U wobble pairs and an A:C mismatch that together constitute a bulge element. The wild-type IAV panhandle directly binds to and activates RIG-I, while panhandle variants with the destabilizing elements eliminated (5′ and 3′ complete constructs, 5′dA10, and 3′i10U) activate RIG-I more efficiently than does the wild type. Whether the IAV promoter region in the corkscrew configuration is able to activate RIG-I remains unknown. The IAV antigenomic promoter region contains two A:C mismatches in close proximity to the 5′ triphosphate which largely disrupt the double-strandedness of the panhandle proximal stem and has been shown to lack RIG-I-activating ability. Synthetic panhandle RNAs stimulating that of rabies virus (RABV) and vesicular stomatitis virus (VSV) have also been shown to potently activate RIG-I.
FIG 2
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.
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