Selective inhibition of miRNA processing by a herpesvirus-encoded miRNA | |
Article | |
关键词: VIRUS; RNA; GENE; BIOGENESIS; PROTEIN; LET-7; CELL; IDENTIFICATION; RECOGNITION; INFECTION; | |
DOI : 10.1038/s41586-022-04667-4 | |
来源: SCIE |
【 摘 要 】
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 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.
【 授权许可】
Free