Selective inhibition of miRNA processing by a herpesvirus-encoded miRNA.

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.

• Authors: 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, Bhupesh K Prusty
• Journal: Nature (Nature) Vol. 605 Issue 7910 Pg. 539-544 (05 2022) ISSN: 1476-4687 [Electronic] England
• PMID: 35508655 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• MicroRNAs

Topics

• Herpesviridae (genetics, metabolism)
• Humans
• Immune Evasion
• MicroRNAs (genetics, metabolism)
• RNA Interference
• RNA Processing, Post-Transcriptional
• Virus Latency (genetics)