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Selective inhibition of microRNA processing by a herpesvirus-encoded microRNA triggers virus reactivation from latency

Please always quote using this URN: urn:nbn:de:bvb:20-opus-267858
  • Herpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation thereof 1,2. A long appreciated, yet elusively defined relationship exists between the lytic-latent switch and viral non-coding RNAs 3,4. Here, we identify miRNA-mediated inhibition of miRNA processing as a novel cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defense and drive the latent-lytic switch. We demonstrate that virus-encodedHerpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation thereof 1,2. A long appreciated, yet elusively defined relationship exists between the lytic-latent switch and viral non-coding RNAs 3,4. Here, we identify miRNA-mediated inhibition of miRNA processing as a novel cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defense and drive the latent-lytic switch. We demonstrate that virus-encoded miR-aU14 selectively inhibits the processing of multiple miR-30 family members by direct interaction with the respective pri-miRNA hairpin loops. Subsequent loss of miR-30 and activation of miR-30/p53/Drp1 axis triggers a profound disruption of mitochondrial architecture, which impairs induction of type I interferons and is necessary for both productive infection and virus reactivation. Ectopic expression of miR-aU14 was sufficient to trigger virus reactivation from latency thereby identifying it as a readily drugable master regulator of the herpesvirus latent-lytic 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 provides exciting therapeutic options for preventing herpesvirus reactivations in HHV-6-associated disorders like myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and Long-COVID.show moreshow less
Metadaten
Author: Thomas Hennig, Archana B. Prusty, Benedikt Kaufer, Adam W. Whisnant, Manivel Lodha, Antje Enders, Julius Thomas, Francesca Kasimir, Arnhild Grothey, Stefanie Herb, Christopher JürgesORCiD, Gunter MeisterORCiD, Florian ErhardORCiD, Lars DölkenORCiD, Bhupesh K. Prusty
URN:urn:nbn:de:bvb:20-opus-267858
Document Type:Preprint
Faculties:Medizinische Fakultät / Institut für Virologie und Immunbiologie
Fakultät für Biologie / Theodor-Boveri-Institut für Biowissenschaften
Fakultät für Chemie und Pharmazie / Lehrstuhl für Biochemie
Language:English
Year of Completion:2021
Edition:submitted version
URL:https://doi.org/10.21203/rs.3.rs-820696/v1
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:HHV-6; Herpesvirus; fusion and fission; latency; miR-30; miRNA processing; mitochondria; type I interferon; virus reactivation
Release Date:2022/04/19
EU-Project number / Contract (GA) number:721016
OpenAIRE:OpenAIRE
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International