Investigation of the Molluscum Contagiosum Virus Protein MC089 as a Novel Inhibitor of Interferon Regulatory Factor 3 Activation

Abstract

Molluscum contagiosum virus (MCV) is a human-specific poxvirus that causes highly common, mild, papular skin lesions. The lesions are notable for exerting minimal to no inflammation but can persist for a long duration without an effective antiviral response from the host. As part of the Poxviridae, MCV encodes multiple potent immunomodulators that target innate immune signaling pathways from early virus sensing to interferon (IFN) and inflammatory responses leading to clearance. Two major families of transcription factors are responsible for driving the immune responses to viruses: the nuclear factor kappa B (NF-kappaB) and the Interferon Regulatory Factor (IRF) families. Whilst NF-kappaB broadly drives both pro-inflammatory and IFN gene expression, IRFs have more direct control over antiviral IFN induction, of which, IRF3 has the strongest role in driving the initial wave of type I IFN (TI-IFN) expression. 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 targets specific IRF3-activation complexes containing IKK epsilon and its scaffold proteins TBKBP1 and NAP1. Additionally, MC089 particularly targets the RIG-I sensing pathway by associating with MAVS on mitochondria. MC089 displays specificity in its inhibition of IRF3 activation, preventing serine 396 phosphorylation and impeding TI-IFN response without affecting phosphorylation of serine 386. This remark, along with MC089 binding specificity to its target proteins, may give novel insights into the regulation of antiviral IRF3 activation.