The C11R Gene, Which Encodes the Vaccinia Virus Growth Factor, Is Partially Responsible for MVA-Induced NF-κB and ERK2 Activation

Abstract

<jats:p>MVA is an attenuated strain of vaccinia virus (VACV) that is a popular vaccine vector. MVA infection activates NF-κB. For 293T cells, it is known that MVA early gene expression activates extracellular signal-regulated kinase 2 (ERK2), resulting in NF-κB activation. However, other viral and cellular mechanisms responsible for this event are ill defined. The data presented here show that the epidermal growth factor receptor (EGFR) is at least one apical trigger in this pathway: ERK2 and NF-κB activation was diminished when MVA infections occurred in cells devoid of the EGFR (CHO K1 cells) or in the presence of a drug that inhibits EGFR activation (AG1478) in 293T cells. The expression of dominant negative Ras or Raf proteins still permitted NF-κB activation, suggesting that a nonclassical EGFR-based signal transduction pathway triggered ERK2–NF-κB activation. C11R is an early gene present in MVA and other orthopoxviruses. It encodes the soluble, secreted vaccinia virus growth factor (VGF), a protein that binds to and stimulates the EGFR. Here it was observed that NF-κB was activated in 293T cells transfected with a plasmid encoding the C11R gene. Silencing by small interfering RNA (siRNA) or deletion of the C11R gene (MVAΔC11R) reduced both MVA-induced ERK2 and NF-κB activation in 293T cells or the keratinocyte line Hacat, suggesting that this mechanism of MVA-induced NF-κB activation may be common for several cell types.</jats:p>

Redundancy complicates the definition of essential genes for vaccinia virus

“…In support of this possibility, deletion of C11R and J2R (encoding thymidine kinase) produces a stronger replication defect than the loss of either gene alone (McCart et al, 2001). At the same time, deletion of C11R from MVA has been shown to slightly decrease activation of the antiviral NFk B response (Martin et al, 2012). Together, these findings highlight the many complex interactions possible amongst VACV genes.…”

Vaccinia E5 is a major inhibitor of the DNA sensor cGAS

“…Among these genes, WR200/B19R is known to encode a type I IFN binding protein (Symons et al, 1995). Although K7, B14, and C11 have been described as vaccinia virulence factors (Benfield et al, 2013;Chen et al, 2008;Martin et al, 2012), and WR199/B18R was reported to encode a host range factor (Liu et al, 2018;Sperling et al, 2009), how they evade the type I IFN pathway is unclear. E4L encodes vaccinia RNA polymerase subunit RPO30 and a intermediate transcription factor (Ahn et al, 1990;Rosales et al, 1994), and is essential for vaccinia life cycle.…”

From Scourge to Cure: Tumour-Selective Viral Pathogenesis as a New Strategy against Cancer

“…Both herpes- and poxviruses activate the EGFR during their replication cycle [104],[105]. For example, VV encodes vaccinia growth factor (VGF), an early secreted protein that binds EGFR and conditions surrounding cells for subsequent viral infection [106].…”

“…Increases in the frequency of mitogenic signals received through receptors such as epidermal growth factor receptor (EGFR) and its main downstream signaling transduction partners, PI3K/AKT and RAS/Mitogen-Activated Protein Kinase Kinase/Mitogen-Activated Protein Kinase (RAS/MEK/MAPK), also drive transformed or infected cell proliferation. Both herpes- and poxviruses activate the EGFR during their replication cycle [104] , [105] . For example, VV encodes vaccinia growth factor (VGF), an early secreted protein that binds EGFR and conditions surrounding cells for subsequent viral infection [106] .…”