Abstract
The nucleus represents a cellular compartment where the discrimination of self from non-self nucleic acids is vital. While emerging evidence establishes a nuclear non-self DNA sensing paradigm, the nuclear sensing of non-self RNA, such as that from nuclear-replicating RNA viruses, remains unexplored. Here, we report the identification of nuclear-resident RIG-I actively involved in nuclear viral RNA sensing. The nuclear RIG-I, along with its cytoplasmic counterpart, senses influenza A virus (IAV) nuclear replication leading to a cooperative induction of type I interferon response. Its activation signals through the canonical signaling axis and establishes an effective antiviral state restricting IAV replication. The exclusive signaling specificity conferred by nuclear RIG-I is reinforced by its inability to sense cytoplasmic-replicating Sendai virus and appreciable sensing of hepatitis B virus pregenomic RNA in the nucleus. These results refine the RNA sensing paradigm for nuclear-replicating viruses and reveal a previously unrecognized subcellular milieu for RIG-I-like receptor sensing.
Highlights
The nucleus represents a cellular compartment where the discrimination of self from non-self nucleic acids is vital
To ensure any observed retinoic acid inducible gene I (RIG-I) localization by immunofluorescence was genuine, RIG-I KO A549 cells were generated by CRISPR/Cas9-mediated genome editing (Supplementary Fig. 1) and the specificity of RIGI antibodies from different sources was carefully monitored by observing RIG-I staining in RIG-I KO A549 cells stimulated with Sendai virus (SeV) (Supplementary Fig. 2a)
The incoming viral ribonucleoprotein (vRNP) immediately associate with RIG-I25,26, whether it leads to RIG-I activation and IFN induction remains unclear
Summary
The nucleus represents a cellular compartment where the discrimination of self from non-self nucleic acids is vital. The constant challenge of the vertebrate cells by invading pathogens drives the evolution of innate immune systems to rapidly detect and respond to non-self molecules, such as the virus-derived nucleic acids[1] Depending on their intracellular localization, distinct germline-encoded pattern-recognition receptors (PRRs) engage specialized adapters to initiate immune signaling cascades from within different cellular compartments. The members of the Flaviviridae family, including tick-borne encephalitis virus and hepatitis C virus, induce the formation of compartmentalized membrane structures to sterically segregate their viral agonists from PRRs15,16 This strategy conceals the viral replication site from the cytosolic RLRs, thereby minimizing the likelihood of non-self RNA sensing. Influenza A virus (IAV) is the most-studied member of the Orthomyxoviridae family whose genome transcription and replication are closely associated with nuclear machinery[19] It stimulates type I IFN expression in infected cells via a nearly strict RIG-I-dependent signaling cascade[11,20]. Our findings unravel a previously unrecognized nuclear pool of RIG-I sensing nuclear viral RNA and implicate a novel subcellular milieu for RLR sensing
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