SIDT2 Transports Extracellular dsRNA into the Cytoplasm for Innate Immune Recognition

Tan A Nguyen; Blake R C Smith; Michelle D Tate; Gabrielle T Belz; Marilou H Barrios; Kirstin D Elgass; Alexandra S Weisman; Paul J Baker; Simon P Preston; Lachlan Whitehead; Alexandra Garnham; Rachel J Lundie; Gordon K Smyth; Marc Pellegrini; Meredith O'Keeffe; Ian P Wicks; Seth L Masters; Craig P Hunter; Ken C Pang

doi:10.1016/j.immuni.2017.08.007

SIDT2 Transports Extracellular dsRNA into the Cytoplasm for Innate Immune Recognition

Immunity. 2017 Sep 19;47(3):498-509.e6. doi: 10.1016/j.immuni.2017.08.007. Epub 2017 Sep 12.

Authors

Tan A Nguyen¹, Blake R C Smith², Michelle D Tate³, Gabrielle T Belz¹, Marilou H Barrios¹, Kirstin D Elgass⁴, Alexandra S Weisman⁵, Paul J Baker¹, Simon P Preston¹, Lachlan Whitehead¹, Alexandra Garnham¹, Rachel J Lundie⁶, Gordon K Smyth⁷, Marc Pellegrini¹, Meredith O'Keeffe⁶, Ian P Wicks¹, Seth L Masters¹, Craig P Hunter⁵, Ken C Pang⁸

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
² The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
³ Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia.
⁴ Monash Micro Imaging, Monash University, Clayton, VIC, Australia.
⁵ Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
⁶ Burnet Institute, Melbourne, VIC, Australia; Biomedicine Discovery Institute, Department Biochemistry & Molecular Biology, Monash University, Clayton, VIC, Australia.
⁷ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; School of Mathematics & Statistics, University of Melbourne, Parkville, VIC, Australia.
⁸ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Murdoch Childrens Research Institute, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia; Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia. Electronic address: pang.k@wehi.edu.au.

Abstract

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.

Keywords: EMCV; HSV; MAVS; SIDT2; bystander immunity; double-stranded RNA; type I interferon; virus infection.

MeSH terms

Animals
Cardiovirus Infections / genetics
Cardiovirus Infections / immunology
Cell Line
Cytoplasm
DEAD Box Protein 58 / metabolism
Disease Models, Animal
Encephalomyocarditis virus / genetics
Encephalomyocarditis virus / immunology
Endosomes / metabolism
Female
Gene Expression
Gene Knockout Techniques
Herpes Simplex / genetics
Herpes Simplex / immunology
Herpesvirus 1, Human / genetics
Herpesvirus 1, Human / immunology
Host-Pathogen Interactions / genetics
Host-Pathogen Interactions / immunology
Immunity, Innate*
Lysosomes / metabolism
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Mice, Knockout
Nucleotide Transport Proteins
Protein Binding
Protein Transport
RNA Transport*
RNA, Double-Stranded / immunology*
RNA, Double-Stranded / metabolism*
RNA, Viral / genetics
RNA, Viral / metabolism
Signal Transduction
Toll-Like Receptor 3 / metabolism

Substances

Membrane Proteins
Nucleotide Transport Proteins
RNA, Double-Stranded
RNA, Viral
Sidt2 protein, mouse
Toll-Like Receptor 3
DEAD Box Protein 58

Abstract

MeSH terms

Substances

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