Sidt2 transports extracellular dsRNA into the cytoplasm for innate immune recognition — ASN Events
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Sidt2 transports extracellular dsRNA into the cytoplasm for innate immune recognition (#85)

Tan A Nguyen 1 2 , Blake RC Smith 1 3 , Michelle D Tate 4 5 , Gabrielle T Belz 1 2 , Marilou H Barrios 1 2 , Kirstin D Elgass 6 , Alexandra S Weisman 7 , Paul J Baker 1 2 , Simon Preston 1 2 , Lachlan Whitehead 1 2 , Alexandra Garnham 1 2 , Rachel J Lundie 8 9 , Gordon K Smyth 1 10 , Marc Pellegrini 1 2 , Meredith O'Keeffe 8 9 , Ian P Wicks 1 2 , Seth L Masters 1 7 , Craig P Hunter 7 , Ken C Pang 1 3 11 12
  1. Walter and Eliza Hall Institute, Parkville, VIC, Australia
  2. Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
  3. Murdoch Children's Research Institute, Parkville
  4. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia
  5. Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia
  6. Monash Micro Imaging, Monash University, Clayton, VIC, Australia
  7. Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, United States
  8. Burnet Institute, Melbourne, VIC, Australia
  9. Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
  10. School of Mathematics & Statistics, University of Melbourne, Parkville, VIC, Australia
  11. Department of Paediatrics, University of Melbourne, Parkville
  12. Department of Psychiatry, University of Melbourne, Parkville

During viral infection, extracellular double stranded RNA (dsRNA) acts as a potent trigger of innate immunity via the production of type I interferons (IFNs). The detection of extracellular dsRNA involves different host cell sensors such as Toll-like receptor 3 (TLR3) and the RIG-I-like receptors (RLRs), RIG-I and MDA-5. TLR3 is located within endo-lysosomes, and is therefore well situated to detect dsRNA that has been taken up from the environment. Internalised dsRNA also activates the cytoplasmic RLRs, implying the existence of a mechanism to transport dsRNA across the endosomal membrane. Interestingly, the RLRs are functionally dominant over TLR-3 in the response to extracellular dsRNA and are critical for immunity to multiple viruses, but how dsRNA escapes from the endosome is unknown. Here we report that Sidt2, a mammalian orthologue of the C. elegans SID-1 dsRNA transporter, is present within the endosomal compartment and co-localises with internalised poly(I:C), a synthetic analogue of dsRNA. Sidt2-deficient mice show impaired production of type I IFNs in response to extracellular poly(I:C) in vivo. These observations suggest a role for Sidt2 in transporting dsRNA from the endosome into the cytoplasm. In support of this, we found that loss of Sidt2 does not affect dsRNA internalization, but instead results in the accumulation of poly(I:C) within the endosomal compartment. In keeping with this, over expression of Sidt2 enhanced endosomal escape of poly(I:C). Sidt2-deficient mice produce less type I IFNs and have increased mortality in response to infection with encephalomyocarditis virus (EMCV) and herpes simplex virus type 1 (HSV-1). Our findings demonstrate a key role for Sidt2 in the endosomal escape of dsRNA and the subsequent induction of innate immunity.

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