PMID- 35508655 OWN - NLM STAT- MEDLINE DCOM- 20220520 LR - 20220531 IS - 1476-4687 (Electronic) IS - 0028-0836 (Linking) VI - 605 IP - 7910 DP - 2022 May TI - Selective inhibition of miRNA processing by a herpesvirus-encoded miRNA. PG - 539-544 LID - 10.1038/s41586-022-04667-4 [doi] AB - Herpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation(1,2). A long appreciated, yet undefined relationship exists between the lytic-latent switch and viral non-coding RNAs(3,4). 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. CI - (c) 2022. The Author(s), under exclusive licence to Springer Nature Limited. FAU - Hennig, Thomas AU - Hennig T AD - Institute for Virology and Immunobiology, Julius-Maximilians-Universitat Wurzburg, Wurzburg, Germany. FAU - Prusty, Archana B AU - Prusty AB AUID- ORCID: 0000-0003-4749-3175 AD - Department of Biochemistry, Theodor Boveri Institute, Biocenter of the University of Wurzburg, Wurzburg, Germany. FAU - Kaufer, Benedikt B AU - Kaufer BB AD - Institute of Virology, Department of Veterinary Medicine at the Freie Universitat Berlin, Berlin, Germany. FAU - Whisnant, Adam W AU - Whisnant AW AUID- ORCID: 0000-0003-2039-2809 AD - Institute for Virology and Immunobiology, Julius-Maximilians-Universitat Wurzburg, Wurzburg, Germany. FAU - Lodha, Manivel AU - Lodha M AUID- ORCID: 0000-0002-0258-1895 AD - Institute for Virology and Immunobiology, Julius-Maximilians-Universitat Wurzburg, Wurzburg, Germany. FAU - Enders, Antje AU - Enders A AUID- ORCID: 0000-0001-8657-8580 AD - Institute for Virology and Immunobiology, Julius-Maximilians-Universitat Wurzburg, Wurzburg, Germany. FAU - Thomas, Julius AU - Thomas J AD - Institute for Virology and Immunobiology, Julius-Maximilians-Universitat Wurzburg, Wurzburg, Germany. FAU - Kasimir, Francesca AU - Kasimir F AUID- ORCID: 0000-0003-2778-4610 AD - Institute for Virology and Immunobiology, Julius-Maximilians-Universitat Wurzburg, Wurzburg, Germany. FAU - Grothey, Arnhild AU - Grothey A AD - Institute for Virology and Immunobiology, Julius-Maximilians-Universitat Wurzburg, Wurzburg, Germany. FAU - Klein, Teresa AU - Klein T AD - Department of Biotechnology and Biophysics, Theodor Boveri Institute, Biocenter of the University of Wurzburg, Wurzburg, Germany. FAU - Herb, Stefanie AU - Herb S AD - Institute for Virology and Immunobiology, Julius-Maximilians-Universitat Wurzburg, Wurzburg, Germany. FAU - Jurges, Christopher AU - Jurges C AUID- ORCID: 0000-0001-5617-6601 AD - Institute for Virology and Immunobiology, Julius-Maximilians-Universitat Wurzburg, Wurzburg, Germany. FAU - Sauer, Markus AU - Sauer M AUID- ORCID: 0000-0002-1692-3219 AD - Department of Biotechnology and Biophysics, Theodor Boveri Institute, Biocenter of the University of Wurzburg, Wurzburg, Germany. AD - Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius Maximilians-Universitat Wurzburg, Wurzburg, Germany. FAU - Fischer, Utz AU - Fischer U AUID- ORCID: 0000-0002-1465-6591 AD - Department of Biochemistry, Theodor Boveri Institute, Biocenter of the University of Wurzburg, Wurzburg, Germany. AD - Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection Research (HZI), Wurzburg, Germany. FAU - Rudel, Thomas AU - Rudel T AUID- ORCID: 0000-0003-4740-6991 AD - Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection Research (HZI), Wurzburg, Germany. AD - Chair of Microbiology, Biocenter of the University of Wurzburg, Wurzburg, Germany. FAU - Meister, Gunter AU - Meister G AUID- ORCID: 0000-0002-2098-9923 AD - Regensburg Center for Biochemistry, University of Regensburg, Regensburg, Germany. FAU - Erhard, Florian AU - Erhard F AUID- ORCID: 0000-0002-3574-6983 AD - Institute for Virology and Immunobiology, Julius-Maximilians-Universitat Wurzburg, Wurzburg, Germany. FAU - Dolken, Lars AU - Dolken L AUID- ORCID: 0000-0002-4651-3544 AD - Institute for Virology and Immunobiology, Julius-Maximilians-Universitat Wurzburg, Wurzburg, Germany. lars.doelken@uni-wuerzburg.de. AD - Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection Research (HZI), Wurzburg, Germany. lars.doelken@uni-wuerzburg.de. FAU - Prusty, Bhupesh K AU - Prusty BK AUID- ORCID: 0000-0001-7051-4670 AD - Institute for Virology and Immunobiology, Julius-Maximilians-Universitat Wurzburg, Wurzburg, Germany. bhupesh.prusty@uni-wuerzburg.de. AD - Chair of Microbiology, Biocenter of the University of Wurzburg, Wurzburg, Germany. bhupesh.prusty@uni-wuerzburg.de. LA - eng GR - ERC_/European Research Council/International PT - Journal Article DEP - 20220504 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (MicroRNAs) SB - IM MH - *Herpesviridae/genetics/metabolism MH - Humans MH - Immune Evasion MH - *MicroRNAs/genetics/metabolism MH - RNA Interference MH - RNA Processing, Post-Transcriptional MH - Virus Latency/genetics EDAT- 2022/05/05 06:00 MHDA- 2022/05/21 06:00 CRDT- 2022/05/04 23:49 PHST- 2021/08/17 00:00 [received] PHST- 2022/03/21 00:00 [accepted] PHST- 2022/05/05 06:00 [pubmed] PHST- 2022/05/21 06:00 [medline] PHST- 2022/05/04 23:49 [entrez] AID - 10.1038/s41586-022-04667-4 [pii] AID - 10.1038/s41586-022-04667-4 [doi] PST - ppublish SO - Nature. 2022 May;605(7910):539-544. doi: 10.1038/s41586-022-04667-4. Epub 2022 May 4.