Adenovirus E4ORF1 activates isoform-specific phosphatidylinositol 3-kinase signaling

ABSTRACT: The human adenovirus serotype 5 E4ORF1 (Ad5E4ORF1) protein promotes primary endothelial cell survival and angiocrine functions by hijacking the cellular phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway. However, the mechanism by which E4ORF1 activates PI3K in vascular cells remains largely unknown. Here we show that Ad5E4ORF1 recruits multiple host scaffold proteins including DLG1, which promotes AKT activation by both Ad5E4ORF1 and cell receptor agonists. Furthermore, Ad5E4ORF1 specifically engages human PI3K isoform p110a-p85b through multi-domain interactions exclusively with p110a. Importantly, various serotypes of E4ORF1 proteins differentially interact with p110a leading to graded AKT activation in endothelial cells. We propose that E4ORF1 specifically recognizes p110a-p85b and allosterically activates PI3K through multiple direct contacts with p110a, setting the stage of endothelial cell survival and homeostatic angiogenic functions.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Endothelial Cell Activation, Umbilical Vein Endothelial Cell, Umbilical Artery Endothelial Cell

SUBMITTER: TuKiet Lam  

LAB HEAD: TuKiet Lam

PROVIDER: PXD069348 | Pride | 2026-01-05

REPOSITORIES: Pride