SIDT2 Transports Extracellular dsRNA into the Cytoplasm for Innate Immune Recognition

• Published in: Immunity (Cambridge, Mass.) Vol. 47; no. 3; pp. 498 - 509.e6
• Main Authors: Nguyen, Tan A., Smith, Blake R.C., Tate, Michelle D., Belz, Gabrielle T., Barrios, Marilou H., Elgass, Kirstin D., Weisman, Alexandra S., Baker, Paul J., Preston, Simon P., Whitehead, Lachlan, Garnham, Alexandra, Lundie, Rachel J., Smyth, Gordon K., Pellegrini, Marc, O’Keeffe, Meredith, Wicks, Ian P., Masters, Seth L., Hunter, Craig P., Pang, Ken C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.09.2017; Elsevier Limited
• Subjects: Animals; bystander immunity; Caenorhabditis elegans; Cardiovirus Infections - genetics; Cardiovirus Infections - immunology; Cell cycle; Cell Line; Compartments; Cytokines; Cytoplasm; DEAD Box Protein 58 - metabolism; Disease Models, Animal; Double-stranded RNA; EMCV; Encephalomyocarditis virus - genetics; Encephalomyocarditis virus - immunology; Endosomes - metabolism; Female; Gene Expression; Gene Knockout Techniques; Herpes simplex; Herpes Simplex - genetics; Herpes Simplex - immunology; Herpes viruses; Herpesvirus 1, Human - genetics; Herpesvirus 1, Human - immunology; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - immunology; HSV; Immune response; Immunity; Immunity, Innate; Infections; Localization; Lysosomes - metabolism; MAVS; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Microscopy; Protein Binding; Protein Transport; Proteins; Ribonucleic acid; RNA; RNA Transport; RNA, Double-Stranded - immunology; RNA, Double-Stranded - metabolism; RNA, Viral - genetics; RNA, Viral - metabolism; SIDT2; Signal Transduction; Toll-Like Receptor 3 - metabolism; Transport; type I interferon; virus infection; Viruses; type I interferon; MAVS; bystander immunity; HSV; double-stranded RNA; EMCV; SIDT2; virus infection
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2017.08.007

Double-stranded RNA (dsRNA) is a common by-product of viral infections and acts as a potent trigger of antiviral immunity. In the nematode C. elegans, sid-1 encodes a dsRNA transporter that is highly conserved throughout animal evolution, but the physiological role of SID-1 and its orthologs remains unclear. Here, we show that the mammalian SID-1 ortholog, SIDT2, is required to transport internalized extracellular dsRNA from endocytic compartments into the cytoplasm for immune activation. Sidt2-deficient mice exposed to extracellular dsRNA, encephalomyocarditis virus (EMCV), and herpes simplex virus 1 (HSV-1) show impaired production of antiviral cytokines and—in the case of EMCV and HSV-1—reduced survival. Thus, SIDT2 has retained the dsRNA transport activity of its C. elegans ortholog, and this transport is important for antiviral immunity. [Display omitted] •SIDT2 is in endo-lysosomes and interacts with internalized double-stranded RNA•SIDT2 promotes escape of endosomal dsRNA and cytoplasmic RLR signaling•During HSV-1 infection, RLR signaling in bystander cells requires SIDT2•Loss of SIDT2 impairs IFN-β production and survival after HSV-1 and EMCV infection Extracellular double-stranded RNA is predominantly sensed by cytosolic RLRs after endocytic uptake, but how it enters the cytoplasm is unknown. Nguyen and colleagues demonstrate that the endo-lysosomal protein SIDT2 transports double-stranded RNA into the cytoplasm for RLR signaling and is required for survival after EMCV infection.