Selective inhibition of miRNA processing by a herpesvirus-encoded miRNA
Thomas Hennig,
Archana B. Prusty,
Benedikt B. Kaufer,
Adam W. Whisnant,
Manivel Lodha,
Antje Enders,
Julius Thomas,
Francesca Kasimir,
Arnhild Grothey,
Teresa Klein,
Stefanie Herb,
Christopher Jürges,
Markus Sauer,
Utz Fischer,
Thomas Rudel,
Gunter Meister,
Florian Erhard,
Lars Dölken () and
Bhupesh K. Prusty ()
Additional contact information
Thomas Hennig: Julius-Maximilians-Universität Würzburg
Archana B. Prusty: Theodor Boveri Institute, Biocenter of the University of Würzburg
Benedikt B. Kaufer: Institute of Virology, Department of Veterinary Medicine at the Freie Universität Berlin
Adam W. Whisnant: Julius-Maximilians-Universität Würzburg
Manivel Lodha: Julius-Maximilians-Universität Würzburg
Antje Enders: Julius-Maximilians-Universität Würzburg
Julius Thomas: Julius-Maximilians-Universität Würzburg
Francesca Kasimir: Julius-Maximilians-Universität Würzburg
Arnhild Grothey: Julius-Maximilians-Universität Würzburg
Teresa Klein: Theodor Boveri Institute, Biocenter of the University of Würzburg
Stefanie Herb: Julius-Maximilians-Universität Würzburg
Christopher Jürges: Julius-Maximilians-Universität Würzburg
Markus Sauer: Theodor Boveri Institute, Biocenter of the University of Würzburg
Utz Fischer: Theodor Boveri Institute, Biocenter of the University of Würzburg
Thomas Rudel: Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection Research (HZI)
Gunter Meister: University of Regensburg
Florian Erhard: Julius-Maximilians-Universität Würzburg
Lars Dölken: Julius-Maximilians-Universität Würzburg
Bhupesh K. Prusty: Julius-Maximilians-Universität Würzburg
Nature, 2022, vol. 605, issue 7910, 539-544
Abstract:
Abstract Herpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation1,2. A long appreciated, yet undefined relationship exists between the lytic–latent switch and viral non-coding RNAs3,4. Here we identify viral microRNA (miRNA)-mediated inhibition of host miRNA processing as a cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defences and drive the switch from latent to lytic virus infection. We demonstrate that virus-encoded miR-aU14 selectively inhibits the processing of multiple miR-30 family members by direct interaction with the respective primary (pri)-miRNA hairpin loops. Subsequent loss of miR-30 and activation of the miR-30–p53–DRP1 axis triggers a profound disruption of mitochondrial architecture. This impairs induction of type I interferons and is necessary for both productive infection and virus reactivation. Ectopic expression of miR-aU14 triggered virus reactivation from latency, identifying viral miR-aU14 as a readily druggable master regulator of the herpesvirus lytic–latent switch. Our results show that miRNA-mediated inhibition of miRNA processing represents a generalized cellular mechanism that can be exploited to selectively target individual members of miRNA families. We anticipate that targeting miR-aU14 will provide new therapeutic options for preventing herpesvirus reactivations in HHV-6-associated disorders.
Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:605:y:2022:i:7910:d:10.1038_s41586-022-04667-4
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DOI: 10.1038/s41586-022-04667-4
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