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 Peter Preston, Lachlan W Whitehead, Alexandra L. Garnham, Rachel J. Lundie, Gordon K Smyth, Marc Pellegrini, Meredith O'Keeffe, Ian Peter Wicks, Seth L. Masters, Craig P. Hunter, Ken C Pang

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16 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)498-509
Number of pages12
JournalImmunity
Volume47
Issue number3
DOIs
Publication statusPublished - 19 Sep 2017

Keywords

  • Bystander immunity
  • Double-stranded RNA
  • EMCV
  • HSV
  • MAVS
  • SIDT2
  • Type I interferon
  • Virus infection

Cite this

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 Peter ; Whitehead, Lachlan W ; Garnham, Alexandra L. ; Lundie, Rachel J. ; Smyth, Gordon K ; Pellegrini, Marc ; O'Keeffe, Meredith ; Wicks, Ian Peter ; Masters, Seth L. ; Hunter, Craig P. ; Pang, Ken C. / SIDT2 Transports Extracellular dsRNA into the Cytoplasm for Innate Immune Recognition. In: Immunity. 2017 ; Vol. 47, No. 3. pp. 498-509.
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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. 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.",
keywords = "Bystander immunity, Double-stranded RNA, EMCV, HSV, MAVS, SIDT2, Type I interferon, Virus infection",
author = "Nguyen, {Tan A.} and Smith, {Blake R.C.} and Tate, {Michelle D.} and Belz, {Gabrielle T} and Barrios, {Marilou H.} and Elgass, {Kirstin D.} and Weisman, {Alexandra S.} and Baker, {Paul J.} and Preston, {Simon Peter} and Whitehead, {Lachlan W} and Garnham, {Alexandra L.} and Lundie, {Rachel J.} and Smyth, {Gordon K} and Marc Pellegrini and Meredith O'Keeffe and Wicks, {Ian Peter} and Masters, {Seth L.} and Hunter, {Craig P.} and Pang, {Ken C}",
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Nguyen, TA, Smith, BRC, Tate, MD, Belz, GT, Barrios, MH, Elgass, KD, Weisman, AS, Baker, PJ, Preston, SP, Whitehead, LW, Garnham, AL, Lundie, RJ, Smyth, GK, Pellegrini, M, O'Keeffe, M, Wicks, IP, Masters, SL, Hunter, CP & Pang, KC 2017, 'SIDT2 Transports Extracellular dsRNA into the Cytoplasm for Innate Immune Recognition', Immunity, vol. 47, no. 3, pp. 498-509. https://doi.org/10.1016/j.immuni.2017.08.007

SIDT2 Transports Extracellular dsRNA into the Cytoplasm for Innate Immune Recognition. / 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 Peter; Whitehead, Lachlan W; Garnham, Alexandra L.; Lundie, Rachel J.; Smyth, Gordon K; Pellegrini, Marc; O'Keeffe, Meredith; Wicks, Ian Peter; Masters, Seth L.; Hunter, Craig P.; Pang, Ken C.

In: Immunity, Vol. 47, No. 3, 19.09.2017, p. 498-509.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - SIDT2 Transports Extracellular dsRNA into the Cytoplasm for Innate Immune Recognition

AU - Nguyen, Tan A.

AU - Smith, Blake R.C.

AU - Tate, Michelle D.

AU - Belz, Gabrielle T

AU - Barrios, Marilou H.

AU - Elgass, Kirstin D.

AU - Weisman, Alexandra S.

AU - Baker, Paul J.

AU - Preston, Simon Peter

AU - Whitehead, Lachlan W

AU - Garnham, Alexandra L.

AU - Lundie, Rachel J.

AU - Smyth, Gordon K

AU - Pellegrini, Marc

AU - O'Keeffe, Meredith

AU - Wicks, Ian Peter

AU - Masters, Seth L.

AU - Hunter, Craig P.

AU - Pang, Ken C

PY - 2017/9/19

Y1 - 2017/9/19

N2 - 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. 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.

AB - 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. 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.

KW - Bystander immunity

KW - Double-stranded RNA

KW - EMCV

KW - HSV

KW - MAVS

KW - SIDT2

KW - Type I interferon

KW - Virus infection

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DO - 10.1016/j.immuni.2017.08.007

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