Abstract
DExD/H-box helicases play essential roles in RNA metabolism, and emerging data suggests that they have additional functions in antiviral immunity across species. However, little is known about this evolutionarily conserved family in antiviral responses in lower species. Here, through isolation of poly(I:C)-binding proteins in amphioxus, an extant basal chordate, we found that DExD/H-box helicases DHX9, DHX15, and DDX23 are responsible for cytoplasmic dsRNA detection in amphioxus. Since the antiviral roles of DDX23 have not been characterized in mammals, we performed further poly(I:C) pull-down assays and found that human DDX23 binds to LMW poly(I:C) through its N-terminal region, suggesting that DDX23 is an evolutionarily conserved dsRNA sensor. Knockdown of human DDX23 enhanced the replication of VSV and reduced the activation of the NF-κB and IRF3. Moreover, when stimulated with poly(I:C) or VSV, human DDX23 translocated from the nucleus to the cytoplasm and formed complexes with TRIF or MAVS to initiate downstream signaling. Collectively, this comparative immunological study not only defined DDX23 as an emerging nuclear pattern recognition receptor (PRR) for the innate sensing of an RNA virus, but also extended the essential role of the DExD/H helicase family in viral RNA sensing from mammals to basal chordates.
Highlights
RNA helicases control nearly every facet of RNA metabolism, including transcription, splicing, miRNA biogenesis, translation, and decay [1,2,3]
DExD/H-box proteins are most recognized for their roles in RNA metabolism, some have important functions in antiviral defense, including mammalian RIG-I/DDX58, MDA5/IFIH1, DHX9, DHX15, DHX36, DDX17, and DDX41 [4,5,6]
Entire gel lanes from the poly(I:C) or the controls were excised from the gels and analyzed by LC-mass spectrometry (LC-MS)
Summary
RNA helicases control nearly every facet of RNA metabolism, including transcription, splicing, miRNA biogenesis, translation, and decay [1,2,3]. DExD/H-box proteins are most recognized for their roles in RNA metabolism, some have important functions in antiviral defense, including mammalian RIG-I/DDX58, MDA5/IFIH1, DHX9, DHX15, DHX36, DDX17, and DDX41 [4,5,6]. It is well-established that RNA helicases preferentially use different adaptor molecules to trigger antiviral responses. A complex of DDX1, DDX21, and DHX36 pairs with TRIF [7]; RIG-I, MDA5, DHX9, and DHX15 use MAVS [6, 8,9,10]; and DHX33 interacts with NLRP3 to DDX23 Is a Novel dsRNA Sensor form the inflammasome complex following stimulation with RNA [11]. MDA5 contributes little to the mDC’s response to poly(I:C), while the DDX1-DDX21-DHX36 complex recognizes poly(I:C) in mDCs [7, 15]
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