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NUDT21 links mitochondrial IPS-1 to RLR-containing stress granules and activates host antiviral defense

Saeko Aoyama-Ishiwatari, View ORCID ProfileTomohiko Okazaki, Shun-ichiro Iemura, Tohru Natsume, View ORCID ProfileYasushi Okada, Yukiko Gotoh
doi: https://doi.org/10.1101/2020.04.09.033597
Saeko Aoyama-Ishiwatari
1Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
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Tomohiko Okazaki
1Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
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  • For correspondence: tokazaki@mol.f.u-tokyo.ac.jp
Shun-ichiro Iemura
2Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo 135-0064, Japan
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Tohru Natsume
2Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo 135-0064, Japan
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Yasushi Okada
3Laboratory for Cell Dynamics Observation, Center for Biosystems Dynamics Research (BDR), RIKEN, Osaka 565-0874, Japan
4Department of Physics, Universal Biology Institute (UBI)
5International Research Center for Neurointelligence (WPI-IRCN), The University of Tokyo, Tokyo 113-0033, Japan
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Yukiko Gotoh
1Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
5International Research Center for Neurointelligence (WPI-IRCN), The University of Tokyo, Tokyo 113-0033, Japan
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Summary

Viral RNA in the cytoplasm of mammalian host cells is recognized by retinoic acid– inducible protein–I (RIG-I)–like receptors (RLRs), which localize to cytoplasmic stress granules (SGs). Activated RLRs associate with the mitochondrial adaptor protein IPS-1, which activates antiviral host defense mechanisms including type I interferon (IFN) induction. It has remained unclear, however, how RLRs in SGs and IPS-1 in the mitochondrial outer membrane associate physically and engage in information transfer. Here we show that NUDT21, an RNA binding protein that regulates alternative transcript polyadenylation, physically associates with IPS-1 and mediates its localization to SGs in response to transfection with poly(I:C), a mimic of viral double-stranded RNA. We found that, despite its well-established function in the nucleus, a fraction of NUDT21 localizes to mitochondria in resting cells and becomes localized to SGs in response to poly(I:C) transfection. NUDT21 was also found to be required for efficient type I IFN induction in response to viral infection. Our results together indicate that NUDT21 links RLRs in SGs to mitochondrial IPS-1 and thereby activates host defense responses to viral infection.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 10, 2020.
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NUDT21 links mitochondrial IPS-1 to RLR-containing stress granules and activates host antiviral defense
Saeko Aoyama-Ishiwatari, Tomohiko Okazaki, Shun-ichiro Iemura, Tohru Natsume, Yasushi Okada, Yukiko Gotoh
bioRxiv 2020.04.09.033597; doi: https://doi.org/10.1101/2020.04.09.033597
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NUDT21 links mitochondrial IPS-1 to RLR-containing stress granules and activates host antiviral defense
Saeko Aoyama-Ishiwatari, Tomohiko Okazaki, Shun-ichiro Iemura, Tohru Natsume, Yasushi Okada, Yukiko Gotoh
bioRxiv 2020.04.09.033597; doi: https://doi.org/10.1101/2020.04.09.033597

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