Selective inhibition of miRNA processing by a herpesvirus-encoded miRNA, 2022, Prusty et al

Discussion in 'Other health news and research' started by Andy, May 5, 2022.

  1. Andy

    Andy Committee Member

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    Abstract

    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.

    Paywall, https://www.nature.com/articles/s41586-022-04667-4
     
  2. Andy

    Andy Committee Member

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  3. InitialConditions

    InitialConditions Senior Member (Voting Rights)

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  4. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    I think this is an important paper to read through, but it is in Nature Nature and not open-access. It may be that the team have now found this mechanism occurs in other herpesvirus family members, including EBV. I'll attempt some summary quotes by section along with a glossary.

    Executive summary —

    HHV6A produces its own microRNA (aka mIR) and by so doing interferes with the host cell's production of its own mIR-30 family members. The loss of mIR-30c leads to upregulation of p53 and therefore DRP1, which causes mitrochondrial fission and also consequently downregulates type I interferon.
     
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  5. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Glossary

    DRP1 - dynamin related protein 1, a GTPase
    GFP - green fluorescent protein
    HHV6A - human herpesvirus type 6A
    JAK/STAT - janus kinase / signal transducer and activator of transcription proteins
    miRNA - microRNA, aka miR (a capitalized "miR-" refers to the mature form of the miRNA, while the uncapitalized "mir-" refers to the pre-miRNA and the pri-miRNA)
    mitoGFP - mitochondrial targetted green fluorescent protein
    p53 - protein product of TP53 tumour suppressor gene, pro-apoptotic
    pre-mIR - precursor microRNA, second step in processing (post-transcription), following asymmetric cleavage of the hairpin loop
    pri-miR - primary microRNA, first step in processing (nuclear transcription), with two limbs connected by a hairpin loop
    RIG-I-MAV - retinoic inducible gene I / mitochondrial antiviral signalling protein
    TSA - trichostatin-A, histone deacetylase inhibitor, induces latent herpesvirus reactivation

    For background on microRNAs see Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation (2018, Frontiers in Endocrinology)
     
    Last edited: May 2, 2023
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  6. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Introduction

    Section - HHV-6 induces mitochondrial fission

     
    Last edited: May 2, 2023
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  7. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Section - HHV-6 inhibits miR-30 processing

    Section - miR-aU14 inhibits miR-30 processing

     
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  8. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Section - miR-aU14 induces mitochondrial fission

     
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  9. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Section - Mechanism of the miRNA processing defect

    Section - miR-aU14 inhibits the interferon response

     
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  10. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Section - miR-aU14 triggers virus reactivation

    Section - Targeting human miRNA processing

     
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  11. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Discussion

     
    Last edited: May 2, 2023
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