YND1 Interacts with CDC55 and Is a Novel Mediator of E4orf4-induced Toxicity

Maoz, Tsofnat; Koren, Roni; Ben-Ari, Inbal; Kleinberger, Tamar

doi:10.1074/jbc.m507281200

Cited by 20 publications

(38 citation statements)

References 52 publications

(59 reference statements)

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“…Predictions of the binding site were based on the solved structure of B55␣ (PDB ID 3dw8), containing a 7-bladed ␤ propeller composed of 7 WD repeats (28). Because the E4orf4 signaling network is highly conserved in evolution from yeast to mammalian cells (10,(13)(14)(15), we looked for evolutionary conserved B55␣ residues that may interact with E4orf4. To do so, BLAST was used to compare B55␣ protein sequences from several organisms, and the results were subjected to multiple sequence alignment.…”

Section: Identification Of Significant Conservedmentioning

confidence: 99%

“…E4orf4-induced cell death is more efficient in oncogene-transformed cells (12), indicating that study of E4orf4 signaling may have implications for cancer therapy. Furthermore, at least part of the E4orf4 signaling network is highly conserved in evolution from yeast to mammalian cells (10,(13)(14)(15), underscoring its importance to cell regulation. Studies of the mechanisms underlying E4orf4 action have revealed several E4orf4 partners, including the B55/B␣ (16) and B56 (17) subunits of protein phosphatase 2A (PP2A), the ATP-utilizing chromatin assembly and modifying factor (ACF) (18), Src family kinases (19,20), the anaphase-promoting complex/cyclosome in the budding yeast (10), a subset of splicing serine/arginine-rich proteins (6), and Ynd1/Golgi uridine diphosphatase (14).…”

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confidence: 99%

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Structure- and Modeling-based Identification of the Adenovirus E4orf4 Binding Site in the Protein Phosphatase 2A B55α Subunit

Horowitz

Sharf

Avital-Shacham

et al. 2013

Journal of Biological Chemistry

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Background:The adenovirus E4orf4 protein must bind protein phosphatase 2A (PP2A) for its functions. Results: The E4orf4 binding site in PP2A was mapped to the ␣1,␣2 helices of the B55␣ subunit. Conclusion: The E4orf4 binding site in PP2A-B55␣ lies above the substrate binding site and does not overlap it. Significance: A novel functional significance was assigned to the ␣1,␣2 helices of the PP2A-B55␣ subunit.

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Section: Identification Of Significant Conservedmentioning

confidence: 99%

mentioning

confidence: 99%

Structure- and Modeling-based Identification of the Adenovirus E4orf4 Binding Site in the Protein Phosphatase 2A B55α Subunit

Horowitz

Sharf

Avital-Shacham

et al. 2013

Journal of Biological Chemistry

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“…This nonclassical mode of programmed cell death is more efficient in oncogenically transformed cells than in normal cells (8), indicating that the study of E4orf4 may have implications for cancer therapy. Furthermore, a major part of the E4orf4 signaling network is highly conserved in evolution from Saccharomyces cerevisiae through Drosophila to mammalian cells (9)(10)(11)(12)(13)(14), underscoring its importance to cell regulation.…”

mentioning

confidence: 99%

“…This screen revealed that yeast nucleoside diphosphatase (Ynd1) contributed to E4orf4-induced toxicity and physically interacted with the viral protein (11). Ynd1 is a Golgi apyrase whose enzymatic activity is required for regulation of nucleotide-sugar import into the Golgi lumen (27,28).…”

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confidence: 99%

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NTPDASE4 Gene Products Cooperate with the Adenovirus E4orf4 Protein through PP2A-Dependent and -Independent Mechanisms and Contribute to Induction of Cell Death

Avital-Shacham

Sharf

Kleinberger

2014

J Virol

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The adenovirus E4orf4 protein induces nonclassical apoptosis in mammalian cells through at least two complementing pathways regulated by the interactions of E4orf4 with protein phosphatase 2A (PP2A) and Src kinases. In Saccharomyces cerevisiae cells, which do not express Src, E4orf4 induces PP2A-dependent toxicity. The yeast Golgi apyrase Ynd1 was found to contribute to E4orf4-mediated toxicity and to interact with the PP2A-B55␣ regulatory subunit. In addition, a mammalian Ynd1 orthologue, the NTPDASE4 gene product Golgi UDPase, was shown to physically interact with E4orf4. Here we report that knockdown of NTPDASE4 suppressed E4orf4-induced cell death. Conversely, overexpression of the NTPDASE4 gene products Golgi UDPase and LALP70 enhanced E4orf4-induced cell killing. We found that similarly to results obtained in yeast, the apyrase activity of mammalian UDPase was not required for its contribution to E4orf4-induced toxicity. The interaction between E4orf4 and UDPase had two consequences: a PP2A-dependent one, resulting in increased UDPase levels, and a PP2A-independent outcome that led to dissociation of large UDPase-containing protein complexes. The present report extends our findings in yeast to E4orf4-mediated death of mammalian cells, and combined with previous results, it suggests that the E4orf4-NTPDase4 pathway, partly in association with PP2A, may provide an alternative mechanism for the E4orf4-Src pathway to contribute to the cytoplasmic death function of E4orf4. IMPORTANCEThe adenovirus E4orf4 protein contributes to regulation of the progression of virus infection from the early to the late phase, and when expressed alone, it induces a unique caspase-independent programmed cell death which is more efficient in cancer cells than in normal cells. The interactions of E4orf4 with cellular proteins that mediate its functions, such as PP2A and Src kinases, are highly conserved in evolution. The results presented here reveal that the NTPDASE4 gene product Golgi UDPase, first discovered to contribute to E4orf4 toxicity in Saccharomyces cerevisiae, associates with E4orf4 and plays a role in induction of cell death in mammalian cells. Details of the functional interaction between E4orf4, PP2A, and the UDPase are described. Identification of the evolutionarily conserved mechanisms underlying E4orf4 activity will increase our understanding of the interactions between the virus and the host cell and will contribute to our grasp of the unique mode of E4orf4-induced cell death.

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Biology of the adenovirus E4orf4 protein: from virus infection to cancer cell death

Kleinberger

2019

FEBS Letters

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The adenovirus (Ad) early region 4 open reading frame 4 (E4orf4) protein is a small 14‐kDa polypeptide endowed with important viral regulatory functions. Although deletion of E4orf4 does not have a major effect on Ad replication due to redundancy among many Ad proteins, E4orf4 provides several functions that improve viral replication. E4orf4 contributes to temporal regulation of virus infection by downregulating early viral gene expression and by altering splicing patterns of Ad mRNAs. It also optimizes the cellular environment for Ad replication by activating the mammalian target of rapamycin pathway to increase viral protein production and by impacting the cell cycle. In addition, E4orf4 participates in the inhibition of the host DNA damage response, promoting the ability of Ad to counteract this antiviral defense mechanism. To fulfill these functions, E4orf4 interacts with numerous cellular proteins, including the major E4orf4 partner, protein phosphatase 2A (PP2A). When expressed alone, outside the context of virus infection, E4orf4 induces an evolutionarily conserved, caspase‐independent, cancer‐selective cell death with many interesting characteristics. This review critically describes E4orf4’s contribution to Ad infection and cancer‐cell death.

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YND1 Interacts with CDC55 and Is a Novel Mediator of E4orf4-induced Toxicity

Cited by 20 publications

References 52 publications

Structure- and Modeling-based Identification of the Adenovirus E4orf4 Binding Site in the Protein Phosphatase 2A B55α Subunit

Structure- and Modeling-based Identification of the Adenovirus E4orf4 Binding Site in the Protein Phosphatase 2A B55α Subunit

NTPDASE4 Gene Products Cooperate with the Adenovirus E4orf4 Protein through PP2A-Dependent and -Independent Mechanisms and Contribute to Induction of Cell Death

Biology of the adenovirus E4orf4 protein: from virus infection to cancer cell death

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