Date of Award
Daniel B. Nichols, Ph.D.
Allan Blake, Ph.D.
Constantine Bitsaktsis, Ph.D.
Angela Klaus, Ph.D.
Heping Zhou, Ph.D.
Molluscum, MC160, MAVS, Virus
The Molluscum Contagiosum Virus (MCV) causes a common persistent, skin infection. Two MCV immune evasion molecules, MCV MC159 and MC160 contain tandem death effector domains (DEDs). DEDs are found in several host proteins including pro-apoptotic proteins Fas-associated Death Domain (FADD) and procaspase-8 and are well characterized in innate immune signaling. MC159 blocks apoptosis induced by both Tumor Necrosis Factor (TNF) and the Fas ligand (FasL) and inhibits activation the host pro-inflammatory transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) (Shisler, 2001; Murao and Shisler 2005). MC160, however, does not inhibit apoptosis, but does dampen TNF-induced NF-κB activation (Shisler, 2001; Nichols and Shisler, 2006). Both MC159 and MC160 inhibit activation of type I interferons induced via the mitochondrial antiviral signaling (MAVS) pathway, an important innate signaling network that senses the presence of a viral double-stranded RNA (dsRNA) and induces an interferon (IFN) response. MC159 interacts with the protein kinases TBK-1 and IKKε. However, the molecular mechanism of MC160 is not well understood. When expressed independently, both the C-terminal domain of MC160 as well as the first DED were reported to inhibit TBK-1 induced IRF-3 activation, whereas the second DED was dispensable (Randall et al., 2013).
The goal of the current project is to identify the molecular mechanism through which MC160 inhibits activation of type I IFNs. We characterized the ability of MC160 constructs to inhibit MAVS- and TBK-1 induced activation of type I IFN. When expressed independently neither MC160 DED1 nor DED2 blocked activation the IFN-β enhancer to the extent of full-length or the MC160 construct that expresses both DEDs. Our current analysis suggests that both DED1 and DED2 are required to fully inhibit activation of type I interferons.
Bouza, Lissette, "The Molluscum Contagiosum Virus MC160 Protein Requires Both Death Effector Domains to Inhibit MAVS- and TBK1-Induced Interferon Activation" (2018). Seton Hall University Dissertations and Theses (ETDs). 2564.
Available for download on Sunday, July 28, 2019