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Volume 105, Issue 8

Molluscum contagiosum virus protein MC089 inhibits interferon regulatory factor 3 activation Open Access

Abstract

Molluscum contagiosum virus (MCV) is a human-specific poxvirus that causes a highly common but mild infection characterized by distinctive and persistent papular skin lesions. These lesions can persist for long periods without an effective clearance response from the host. MCV, like all poxviruses, encodes multiple known immunosuppressive proteins which target innate immune signalling pathways involved in viral nucleic acid sensing, interferon production and inflammation which should trigger antiviral immunity leading to clearance. Two major families of transcription factors responsible for driving the immune response to viruses are the NF-κB and the interferon regulatory factor (IRF) families. While NF-κB broadly drives pro-inflammatory gene expression and IRFs chiefly drive interferon induction, both collaborate in transactivating many of the same genes in a concerted immune response to viral infection. Here, we report that the MCV protein MC089 specifically inhibits IRF activation from both DNA- and RNA-sensing pathways, making it the first characterized MCV inhibitor to selectively target IRF activation to date. MC089 interacts with proteins required for IRF activation, namely IKKε, TBKBP1 and NAP1. Additionally, MC089 targets RNA sensing by associating with the RNA-sensing adaptor protein mitochondrial antiviral-signalling protein on mitochondria. MC089 displays specificity in its inhibition of IRF3 activation by suppressing immunostimulatory nucleic acid-induced serine 396 phosphorylation without affecting the phosphorylation of serine 386. The selective interaction of MC089 with IRF-regulatory proteins and site-specific inhibition of IRF3 phosphorylation may offer a tool to provide novel insights into the biology of IRF3 regulation.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): IKKε , innate immunity , MAVS , MC089 , molluscum contagiosum virus , NAP1 and TBKBP1
Funding
This study was supported by the:
  • Helmholtz Association's Initiative and Networking Fund (Award KA1-Co-02, “COVIPA”)
    • Principle Award Recipient: AndreasPichlmair
  • German research foundation (Award TRR179/TP10, TRR237/A07 and TRR353/B04)
    • Principle Award Recipient: AndreasPichlmair
  • Science Foundation Ireland (Award 19/FFP/6848 - 210295-16377)
    • Principle Award Recipient: GarethBrady
© 2024 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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Molluscum contagiosum virus protein MC089 inhibits interferon regulatory factor 3 activation
J. Gen. Virol. 105, 002015 (2024); https://doi.org/10.1099/jgv.0.002015
/content/journal/jgv/10.1099/jgv.0.002015
/content/journal/jgv/10.1099/jgv.0.002015
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