Fig. 6
Mpox manipulation and activation of proviral signaling via AKT, Wnt, and STAT3 signaling pathways. (A) Wnt signaling. Vaccinia virus protein A49 activates Wnt signaling by targeting the E3 ligase β-TrCP, inhibiting the β-catenin degradation complex. This leads to β-catenin accumulation and promotes TCF/LEF transcriptional activation. GSK3β inhibition by the Wnt pathway prevents β-catenin phosphorylation, allowing its cytoplasmic accumulation. Subsequently, β-catenin translocates into the nucleus to activate gene expression by binding TCF/LEF transcription factors. (B) AKT signaling. AKT phosphorylation and activation are facilitated by mammalian targets of rapamycin complex 2 (mTORC2) and phosphoinositide-dependent protein kinase 1 (PDK1 (C) STAT3 signaling. Mpox protein D3R (analogous to Vaccinia virus protein VGF) activates STAT3 function through regulated kinases like ERK, inducing non-canonical phosphorylation of STAT3 at S727 in a D3R(VGF)-dependent manner. Red arrows and boxes indicate proviral signaling pathways and proteins, while green arrows and boxes highlight antiviral signaling pathways, proteins, and potential therapeutic drugs targeting these pathways.
