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Endocytosed dsRNAs induce lysosomal membrane permeabilization that allows cytosolic dsRNA translocation for Drosophila RNAi responses

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Listed:
  • Tsubasa Tanaka

    (Kumamoto University
    Kumamoto University)

  • Tamaki Yano

    (Tohoku University)

  • Shingo Usuki

    (Kumamoto University)

  • Yoko Seo

    (Kumamoto University
    Kumamoto University)

  • Kento Mizuta

    (Kumamoto University
    Kumamoto University)

  • Maho Okaguchi

    (Kumamoto University
    Kumamoto University)

  • Maki Yamaguchi

    (Kumamoto University
    Kumamoto University)

  • Kazuko Hanyu-Nakamura

    (Kumamoto University)

  • Noriko Toyama-Sorimachi

    (The University of Tokyo (IMSUT))

  • Katja Brückner

    (University of California San Francisco)

  • Akira Nakamura

    (Kumamoto University
    Kumamoto University)

Abstract

RNA interference (RNAi) is a gene-silencing mechanism triggered by the cytosolic entry of double-stranded RNAs (dsRNAs). Many animal cells internalize extracellular dsRNAs via endocytosis for RNAi induction. However, it is not clear how the endocytosed dsRNAs are translocated into the cytosol across the endo/lysosomal membrane. Herein, we show that in Drosophila S2 cells, endocytosed dsRNAs induce lysosomal membrane permeabilization (LMP) that allows cytosolic dsRNA translocation. LMP mediated by dsRNAs requires the lysosomal Cl−/H+ antiporter ClC-b/DmOstm1. In clc-b or dmostm1 knockout S2 cells, extracellular dsRNAs are endocytosed and reach the lysosomes normally but fail to enter the cytosol. Pharmacological induction of LMP restores extracellular dsRNA-directed RNAi in clc-b or dmostm1-knockout cells. Furthermore, clc-b or dmostm1 mutant flies are defective in extracellular dsRNA-directed RNAi and its associated antiviral immunity. Therefore, endocytosed dsRNAs have an intrinsic ability to induce ClC-b/DmOstm1-dependent LMP that allows cytosolic dsRNA translocation for RNAi responses in Drosophila cells.

Suggested Citation

  • Tsubasa Tanaka & Tamaki Yano & Shingo Usuki & Yoko Seo & Kento Mizuta & Maho Okaguchi & Maki Yamaguchi & Kazuko Hanyu-Nakamura & Noriko Toyama-Sorimachi & Katja Brückner & Akira Nakamura, 2024. "Endocytosed dsRNAs induce lysosomal membrane permeabilization that allows cytosolic dsRNA translocation for Drosophila RNAi responses," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51343-4
    DOI: 10.1038/s41467-024-51343-4
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    References listed on IDEAS

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    1. Yoshinori Kawamura & Kuniaki Saito & Taishin Kin & Yukiteru Ono & Kiyoshi Asai & Takafumi Sunohara & Tomoko N. Okada & Mikiko C. Siomi & Haruhiko Siomi, 2008. "Drosophila endogenous small RNAs bind to Argonaute 2 in somatic cells," Nature, Nature, vol. 453(7196), pages 793-797, June.
    2. Maria-Carla Saleh & Michel Tassetto & Ronald P. van Rij & Bertsy Goic & Valérie Gausson & Bassam Berry & Caroline Jacquier & Christophe Antoniewski & Raul Andino, 2009. "Antiviral immunity in Drosophila requires systemic RNA interference spread," Nature, Nature, vol. 458(7236), pages 346-350, March.
    3. Philipp F. Lange & Lena Wartosch & Thomas J. Jentsch & Jens C. Fuhrmann, 2006. "ClC-7 requires Ostm1 as a β-subunit to support bone resorption and lysosomal function," Nature, Nature, vol. 440(7081), pages 220-223, March.
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