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. Author manuscript; available in PMC: 2021 May 15.
Published in final edited form as: Clin Cancer Res. 2020 Mar 5;26(10):2381–2392. doi: 10.1158/1078-0432.CCR-19-3420

Fig. 5. Graphical abstract of the study showing mechanism of HSV-1 induced NOTCH activation.

Fig. 5

Infection of glioma cells with oHSV converts it into a signal sending cell that engages with adjacent signal receiving cell to promote gamma secretase mediated cleavage of NOTCH receptor to initiate NOTCH activation in bottom uninfected signal receiving cell. Image shows two adjacent tumor cells (top is infected and bottom cell is uninfected). Upon HSV-1 infection (top cell) virus encoded microRNA-H16 (miR-H16) targets FIH-1 3’UTR (green) which results in reduced amount of FIH-1 protein (faded green in top cell). FIH-1, normally binds and sequester mind bomb 1 (Mib1, shown in orange) which is known to ubiquitinate (green dot) Notch ligand (blue NOTCH ligand at the bottom of the top cell) bound to NOTCH receptor on adjacent cell. Reduction of FIH-1 release Mib1 to ubiquitinate NOTCH ligands. Ubiquitinated NOTCH ligand then traffics to endosomes, causing a physical pull that then exposes NOTCH receptor proteolytic cleavage sites, and cleavage by a disintegrin and metalloprotease (ADAM) Protease and γ secretase (scissors in bottom cell) resulting in eventual release of NOTCH intracellular domain (NICD). Upon release, NICD traffics to the nucleus to initiate NOTCH target gene transcription.