Nuclear hnRNPA2B1 initiates and amplifies the innate immune response to DNA viruses
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TLDR
Heterogeneous nuclear ribonucleoprotein A2B1 was found to bind viral DNA in the cell nucleus during herpes simplex virus–1 (HSV-1) infection and its relationship with known cytosolic stimulator of interferon genes (STING)–dependent DNA sensors such as cyclic GAMP synthase (cGAS).Abstract:
INTRODUCTION Recognition of pathogen-derived nucleic acids by host cells is an evolutionarily conserved mechanism that induces immune defense responses to microbial infections. Most DNA viruses direct their genomic DNA into host cell nuclei, which can serve as an important molecular signature of DNA virus infection. However, little is known about the nuclear surveillance mechanisms for viral nucleic acids. RATIONALE Virus-induced type I interferon (IFN-I) expression depends on the TANK-binding kinase 1–interferon regulatory factor 3 (TBK1–IRF3) activation. We reasoned that nuclear DNA sensors may translocate to the cytoplasm to activate the TBK1–IRF3 pathway after recognizing viral DNA in the nucleus. Thus, we screened nuclear proteins that bound viral DNA and translocated from the nucleus to the cytoplasm after viral infection. Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) was identified as a potential DNA sensor. We then conducted a series of in vivo and in vitro experiments to probe the biological importance and activation mechanisms of hnRNPA2B1. Additionally, we explored its relationship with known cytosolic stimulator of interferon genes (STING)–dependent DNA sensors such as cyclic GAMP synthase (cGAS). RESULTS hnRNPA2B1 was found to bind viral DNA in the cell nucleus during herpes simplex virus–1 (HSV-1) infection. It then translocated to the cytoplasm and activated TBK1 through the tyrosine kinase Src. Accordingly, hnRNPA2B1 knockdowns and deficiency resulted in impaired DNA virus– but not RNA virus–induced IFN-I production and prolonged viral replication. The production of proinflammatory cytokines such as tumor necrosis factor–α (TNF-α) and interleukin-6 (IL-6) was unaffected. hnRNPA2B1 became dimerized after HSV-1 infection. Mutation of the dimer interface abrogated its nucleocytoplasmic translocation upon HSV-1 infection. Thus, hnRNPA2B1 dimerization is required for its nucleocytoplasmic translocation. Additionally, hnRNPA2B1 was demethylated at Arg226 after HSV-1 infection, which led to its activation and the subsequent initiation of IFN-β expression. This demethylation was catalyzed by the arginine demethylase JMJD6. hnRNPA2B1 with dimer interface mutation was unable to associate with JMJD6 after HSV-1 infection and showed increased amounts of arginine methylation compared to full-length hnRNPA2B1, indicating that dimerization was required for its demethylation. To probe the relationship between hnRNPA2B1 and the recognized DNA sensor pathways, we found that the overexpression of hnRNPA2B1 increased HSV-1–induced TBK1 activation and Ifnb1 expression in Cgas–/– L929 cells. Thus, hnRNPA2B1 could induce IFN-I in a cGAS-independent manner at least in part. This is consistent with earlier evidence suggesting the existence of other IFN-I–initiating molecules in the innate response against DNA virus. Wild-type macrophages showed higher and more sustained Ifnb1 expression than Hnrnpa2b1–/– macrophages in response to DNA viruses. Thus, hnRNPA2B1 was required for fully activating type I interferon production against DNA viruses mediated by cGAS, interferon-γ–inducible protein 16 (IFI16), and STING pathways. Mechanistically, hnRNPA2B1 bound CGAS, IFI16,and STING mRNAs and promoted their nucleocytoplasmic trafficking to amplify cytoplasmic innate sensor signaling. The translation of these mRNAs was impaired in the absence of hnRNPA2B1 after HSV-1 infection. hnRNPA2B1 was constitutively associated with fat mass and obesity-associated protein (FTO). This association was abrogated after HSV-1 infection. By this means, hnRNPA2B1 promoted the N6-methyladenosine (m6A) modification and nucleocytoplasmic trafficking of CGAS, IFI16,and STING mRNAs. Thus, hnRNPA2B1 facilitates the efficient induction of antiviral IFN-I production mediated by cGAS, IFI16, and STING. CONCLUSION We identified hnRNPA2B1 as an innate sensor that initiates type I IFN production upon DNA virus infection in the nucleus. hnRNPA2B1 also amplifies type I IFN responses by directly enhancing STING-dependent cytosolic DNA sensing pathways.read more
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