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. 2020 Nov;19(22):2963-2981.
doi: 10.1080/15384101.2020.1836441. Epub 2020 Oct 25.

The adenoviral protein E4orf4: a probing tool to decipher mechanical stress-induced nuclear envelope remodeling in tumor cells

Kévin Jacquet  1   2 , Marc-Antoine Rodrigue  1   2 , Darren E Richard  1   3   4 , Josée N Lavoie  1   2   3
Affiliations

The adenoviral protein E4orf4: a probing tool to decipher mechanical stress-induced nuclear envelope remodeling in tumor cells

Kévin Jacquet et al. Cell Cycle. 2020 Nov.

Abstract

The human adenovirus (Ad) type 2/5 early region 4 (E4) ORF4 protein (E4orf4) exerts a remarkable tumor cell-selective killing activity in mammalian cells. This indicates that E4orf4 can target tumor cell-defining features and is a unique tool to probe cancer cell vulnerabilities. Recently, we found that E4orf4, through an interaction with the polarity protein PAR3, subverts nuclear envelope (NE) remodeling processes in a tumor cell-selective manner. In this Perspective, we outline mechanical signals that modify nuclear dynamics and tumor cell behavior to highlight potential mechanisms for E4orf4's tumoricidal activity. Through an analysis of E4orf4's cellular targets, we define a protein subnetwork that comprises phosphatase systems interconnected to polarity protein hubs, which could contribute to enhanced NE plasticity. We infer that elucidating E4orf4's protein network at a functional level could uncover key mechanisms of NE remodeling that define the tumor cell phenotype.

Keywords: Nuclear envelope; actin; cancer vulnerability; cellular contractility; nuclear rupture and repair; polarity proteins.

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Conflict of interest statement

No potential conflict of interest was reported by the authors.

Figures

Figure 1.
Figure 1.
Migration-induced NE rupture and mechanisms of force transmission to the nucleus by different types of NE-associated actin cables
Figure 2.
Figure 2.
E4orf4's tumoricidal hallmark features
Figure 3.
Figure 3.
E4orf4’s protein network identified by AP-MS analyses
Figure 4.
Figure 4.
Schematics of E4orf4-associated PPP-regulatory proteins, and their relationships to the Hippo pathway and PAR complex network
See this image and copyright information in PMC

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