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Selective inhibition of miRNA 1 processing by a herpesvirus encoded miRNA

Please always quote using this URN: urn:nbn:de:bvb:20-opus-267862
  • 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 thus far unknown cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defense and drive the lytic-latent switch. We demonstrate thatHerpesviruses 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 thus far unknown cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defense and drive the lytic-latent 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 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 drugable 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 provides exciting therapeutic options for preventing herpesvirus reactivations in HHV-6-associated disorders.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-267862
Document Type:Preprint
Faculties:Medizinische Fakultät / Institut für Virologie und Immunbiologie
Fakultät für Biologie / Theodor-Boveri-Institut für Biowissenschaften
Fakultät für Biologie / Rudolf-Virchow-Zentrum
Fakultät für Chemie und Pharmazie / Lehrstuhl für Biochemie
Language:English
Year of Completion:2022
Edition:accepted version
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:HHV-6A; Herpesvirus; fusion and fission; latency; miR-30; miRNA processing; mitochondria; type I interferon; virus reactivation
Release Date:2024/06/12
EU-Project number / Contract (GA) number:721016
EU-Project number / Contract (GA) number:677673
OpenAIRE:OpenAIRE
Licence (German):License LogoDeutsches Urheberrecht