Publikationsdatenbank

Selective inhibition of miRNA processing by a herpesvirus-encoded miRNA (2022)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Hennig, Thomas

Prusty, Archana B.

Kaufer, Benedikt B. (WE 5)

Whisnant, Adam W.

Lodha, Manivel

Enders, Antje

Thomas, Julius

Kasimir, Francesca

Grothey, Arnhild

Klein, Teresa

Herb, Stefanie

Jürges, Christopher

Sauer, Markus

Fischer, Utz

Rudel, Thomas

Meister, Gunter

Erhard, Florian

Dölken, Lars

Prusty, Bhupesh K.

Quelle

Nature : the international journal of science

Bandzählung: 605

Seiten: 539 – 544

ISSN: 0028-0836

Sprache

Englisch

Verweise

URL (Volltext): https://www.nature.com/articles/s41586-022-04667-4

DOI: 10.1038/s41586-022-04667-4

Pubmed: 35508655

Kontakt

Institut für Virologie

Robert-von-Ostertag-Str. 7-13
14163 Berlin
+49 30 838 51833
virologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

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.