Targeting of Tumor Cells by the Adenovirus E4orf4 protein via Par3 Polarity Protein-Regulated Nuclear Envelope Rupture

ABSTRACT: The protein product of the Early region 4 open reading frame 4 (E4orf4) of human adenovirus 2 is reported to exhibit a tumor-selective cell killing activity. Here, we show that E4orf4’s tumoricidal activity correlated with changes in perinuclear actomyosin contractility that are controlled by an interaction with the Par3 polarity protein. Surprisingly, E4orf4 enhanced apical-basal polarity in non-transformed mammary epithelial cells. In contrast, in tumorigenic cells, it induced a high incidence of actin-dependent nuclear bleb rupture. This process, which was regulated by the linker of nucleoskeleton and cytoskeleton (LINC) complex, promoted nuclear efflux of E4orf4 and the breakdown of the nuclear compartment. Significantly, Par3 also regulated the incidence of transient nuclear envelope rupture due to the reduced nuclear rigidity in cells depleted of lamins, in absence of E4orf4. Thus, using E4orf4 as a probing tool, we uncovered a so far un-appreciated role for Par3 in controlling the actin-dependent forces acting on the nuclear envelope to remodel nuclear shape, which might be a defining feature of tumor cells that is harnessed by E4orf4.

INSTRUMENT(S): TripleTOF 5600, QSTAR

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

DISEASE(S): Breast Cancer

SUBMITTER: Kevin Jacquet  

LAB HEAD: Josée, N., Lavoie

PROVIDER: PXD014329 | Pride | 2020-03-19

REPOSITORIES: Pride