Abstract
During adenovirus (Ad) replication the Ad E4orf4 protein regulates progression from the early to the late phase of infection. However, when E4orf4 is expressed alone outside the context of the virus it induces a non-canonical mode of programmed cell death, which feeds into known cell death pathways such as apoptosis or necrosis, depending on the cell line tested. E4orf4-induced cell death has many interesting and unique features including a higher susceptibility of cancer cells to E4orf4-induced cell killing compared with normal cells, caspase-independence, a high degree of evolutionary conservation of the signaling pathways, a link to perturbations of the cell cycle, and involvement of two distinct cell death programs, in the nucleus and in the cytoplasm. Several E4orf4-interacting proteins including its major partners, protein phosphatase 2A (PP2A) and Src family kinases, contribute to induction of cell death. The various features of E4orf4-induced cell killing as well as studies to decipher the underlying mechanisms are described here. Many explanations for the cancer specificity of E4orf4-induced cell death have been proposed, but a full understanding of the reasons for the different susceptibility of cancer and normal cells to killing by E4orf4 will require a more detailed analysis of the complex E4orf4 signaling network. An improved understanding of the mechanisms involved in this unique mode of programmed cell death may aid in design of novel E4orf4-based cancer therapeutics.
Highlights
The adenovirus (Ad) Early region 4 open-reading-frame 4 (E4orf4) protein is a regulator of the progression of Ad infection from the early to the late phase
The results suggest that E4orf4 initiates caspase-independent signaling that can be linked to various cell death pathways, such as caspase-dependent apoptosis or mitotic catastrophe-mediated necrosis
It has been shown that the most typical morphologies associated with E4orf4-induced cell death include membrane blebbing, nuclear condensation and cell detachment, whereas morphologies associated with classical apoptosis such as DNA fragmentation, caspase activation, phosphatidylserine externalization, or changes in mitochondrial membrane potential do not always accompany E4orf4-induced cell killing [23,40,42]
Summary
The adenovirus (Ad) Early region 4 open-reading-frame 4 (E4orf4) protein is a regulator of the progression of Ad infection from the early to the late phase. Mutations in the E4orf sequence that reduced association of E4orf with a PP2A phosphatase activity by at least two-fold and impaired E4orf4-induced cell death E4orf4-PP2A interaction more than two-fold but were deficient in induction of cell death (‘class II mutants’) are shown below the sequence in dark red. Phosphatases of the PP2A group are Ser/Thr phosphatases, which are involved in most cellular processes These enzymes contain three subunits: one of two isoforms of a catalytic C subunit encoded by PPP2CA and PPP2CB, one of two isoforms of a scaffolding A subunit encoded by PPP2R1A and PPP2R1B, and one of twenty-three regulatory B subunits belonging to four unrelated gene families, each containing several isoforms (B/B55: PPP2R2APPP2R2D, B’/B56: PPP2R5A-PPP2R5E, B’’: PPP2R3A-PPP2R3C, and B’’’: STRN, STRN3, STRN4). All E4orf activities during virus infection that are known to date require an interaction between PP2A and the viral protein [2,3,5,7,11,15]
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