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

Tsubasa Tanaka, Tamaki Yano, Shingo Usuki, Yoko Seo, Kento Mizuta, Maho Okaguchi, Maki Yamaguchi, Kazuko Hanyu-Nakamura, Noriko Toyama-Sorimachi, Katja Brückner and Akira Nakamura ()
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Tsubasa Tanaka: Kumamoto University
Tamaki Yano: Tohoku University
Shingo Usuki: Kumamoto University
Yoko Seo: Kumamoto University
Kento Mizuta: Kumamoto University
Maho Okaguchi: Kumamoto University
Maki Yamaguchi: 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

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51343-4

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