REGULATION OF NUCLEAR RIG-I MEDIATED INTERFERON SIGNALING BY DUSP11 DURING INFLUENZA A VIRUS INFECTION

Influenza A virus (IAV) poses a continuous public health threat owing to its ability of frequent antigenic drift and shift. Seasonal flu outbreaks and periodic pandemics cause significant morbidity and mortality, imposing substantial global economic burden. During the course of evolution, mammals have developed cellular defense mechanisms to combat pathogens, with the innate immune system serving as the first line of defense. The swift response of innate immunity against the invading pathogen triggers an effective antiviral response, while priming specific adaptive immunity. Recognition of IAV by the innate immune system involves various pattern recognition receptors (PRRs), notably the retinoic acid-inducible gene I (RIG-I), which plays a crucial role in initiating the type I interferon (IFN) response against IAV. RIG-I has previously been characterized as a cytoplasmic viral RNA sensor that recognizes short double-stranded RNA harboring a 5’-PPP/PP moiety. Despite having a single-stranded RNA genome, RIG-I detects IAV via its, double-stranded, 5’-PPP bearing panhandle structure, created by partial complementarity of the genomic RNA extremities.\n\nNotably, IAV replicates in the nucleus, raising the question of how the cytoplasmic RNA sensor RIG-I detects a nuclear-replicating virus. To unravel this mystery, Liu et al. investigated the spatiotemporal dynamics of IAV detection by RIG-I and identified a nuclear-resident fraction of RIG-I responsible for sensing IAV replication within the nucleus. The nuclear RIG-I (nRIG-I) -mediated IAV sensing initiates an antiviral IFN signaling in a mitochondrial antiviral signaling protein (MAVS) dependent manner. These findings have redefined the paradigm of RNA sensing for nuclear-replicating viruses, unveiling a previously unknown subcellular context for RIG-I-like receptor sensing. However, the precise mechanisms governing the regulation of nRIG-I signaling during IAV infection have remained elusive until now.\n\nThis study presents a revelation that centers on the role of RNA triphosphatase dual specificity phosphatase 11 (DUSP11) in the negative regulation of nRIG-I-mediated IFN production, promoting IAV infection. DUSP11 belongs to a subfamily of protein tyrosine phosphatases known for dephosphorylating serine/threonine/tyrosine residues on protein substrates. Interestingly, DUSP11 lacks the N-terminal domain that typically confers specificity for protein substrates; instead, it exhibits a strong affinity for 5’-PPP/PP bearing RNA, dephosphorylating them to 5’ monophosphate. Crucially, some of the host transcripts, especially those transcribed by RNA polymerase III, are tri-phosphorylated at the 5’end and possess complex secondary structures enabling them to activate PRRs such as RIG-I. DUSP11's catalytic action on these triphosphorylated transcripts prevents an aberrant inflammatory response in the absence of genuine pathogenic stimuli. However, 5′-PPP RNAs are a characteristic feature of viral RNA genomes, prompting the viruses to exploit DUSP11 catalytic activity to modify their RNA and evading detection by the innate immune system.\n\nIn this study, we show that IAV infection orchestrates the recruitment of DUSP11 into the nucleus, where it exerts its influence on viral RNA. Specifically, DUSP11 acts as an editor of viral RNA by removing 5’-terminal diphosphates. This strategic editing process enables the viral RNA to evade detection by nRIG-I, effectively preventing its activation and the subsequent initiation of an IFN response. The mechanism driving the nuclear translocation of DUSP11 appears to hinge on its interaction with the viral nucleoprotein, the interaction probably mediated by specific amino acid residues, Y99 and Y100 in DUSP11, and, P477 and F479 in NP. Mutant DUSP11s (Y99A/Y100A) are unable to translocate to nucleus upon IAV infection, whereas, IAVs carrying mutant NP (P477A/F479A) are unable to recruit DUSP11 into the nucleus, provoke higher levels of IFN production and exhibit attenuation in replication. Interestingly, this attenuation can be rescued by the introduction of nuclear-targeted DUSP11.\n\nCollectively, these findings reveal an ingenious compartmentalization strategy employed by IAV to evade recognition by nRIG-I, thereby evading the host's immune response. This not only adds a new layer of complexity to our understanding of host-virus interactions during IAV infection but also underscores the crucial role of DUSP11 in shaping the outcome of this battle. Targeting DUSP11 could hold promise as a novel approach to bolster the host's defenses against IAV and potentially other viruses employing similar evasion tactics.

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