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 (Corresponding Author), Bhupesh K. Prusty (Corresponding Author)

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)539-544
Number of pages6
JournalNature
Volume605
Issue number7910
DOIs
Publication statusPublished - 19 May 2022
Externally publishedYes

Field of Science*

  • 3.3 Health sciences
  • 1.6 Biological sciences
  • 3.1 Basic medicine

Publication Type*

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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