The adenovirus E4-ORF4 splicing enhancer protein interacts with a subset of phosphorylated SR proteins

Nilsson, Camilla; Petersen-Mahrt, Svend K.; Durot, Céline; Shtrichman, Ronit; Krainer, Adrian R.; Kleinberger, Tamar; Akusjärvi, Göran

doi:10.1093/emboj/20.4.864

Cited by 86 publications

(70 citation statements)

References 46 publications

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“…In support of such a conclusion we have previously shown that the regulated activation of IIIa splicing does not require cis competition in vitro (22). Also, our previous results have suggested that IIIa splicing is actively repressed in early infected cells by SR proteins binding to the 3RE (10), a repression that is relieved at the late phase of infection by a virus-induced dephosphorylation of SR proteins (23,24). Furthermore, the 3VDE, which binds U2AF inefficiently (11,12), adds to the low activity of IIIa splicing at early times of infection.…”

Section: Discussionmentioning

confidence: 54%

L4-33K, an Adenovirus-encoded Alternative RNA Splicing Factor

Törmänen¹,

Backström²,

Carlsson

et al. 2006

Journal of Biological Chemistry

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Splicing of the adenovirus IIIa mRNA is subjected to a strict temporal regulation during virus infection such that efficient IIIa 3 splice site usage is confined to the late phase of the infectious cycle. Here we show that the adenovirus L4-33K protein functions as a virus-encoded RNA splicing factor that preferentially activates splicing of transcripts with a weak 3 splice site sequence context, a sequence configuration that is shared by many of the late adenovirus 3 splice sites. Furthermore, we show that L4-33K activates IIIa splicing through the IIIa virus infection-dependent splicing enhancer element (3VDE). This element was previously shown to be the minimal element, both necessary and sufficient, for activation of IIIa splicing in the context of an adenovirus-infected cell. L4-33K stimulates an early step in spliceosome assembly and appears to be the only viral protein necessary to convert a nuclear extract prepared from uninfected HeLa cells to an extract with splicing properties very similar to a nuclear extract prepared from adenovirus lateinfected cells. Collectively, our results suggest that L4-33K is the key viral protein required to activate the early to late switch in adenovirus major late L1 alternative splicing.Most late adenovirus proteins are translated from mRNAs originating from the major late transcription unit (MLTU), 3 which extends from the major late promoter (MLP) at coordinate 16.8 to a termination signal close to the right-hand end of the genome (reviewed in Ref. 1). The ϳ28,000-nucleotide pre-mRNA expressed from the MLTU becomes polyadenylated at one of five possible sites, generating five families of mRNAs with co-terminal 3Ј-ends (L1-L5; Fig. 1A). Following selection of a poly(A) site, the primary transcript is spliced in such a way that each mature mRNA receives a common set of three short 5Ј-leader segments, the tripartite leader (Fig. 1A). This leader is then spliced to one of several alternative 3Ј splice sites, generating a total of more than 20 cytoplasmic mRNAs.The accumulation of mRNA from the MLTU is subjected to a temporal regulation at the levels of transcription elongation, poly(A) site choice and alternative 3Ј splice site selection (reviewed in Ref. 1). Thus, during the early phase of infection the MLP is active at a level comparable with the other early transcription units, whereas the same promoter accounts for most of the transcriptional activity at late times of infection (2, 3). However, at early times transcription initiated at the MLP decreases gradually over a large region beginning after the L1 unit, with few RNA polymerases extending beyond the L3 polyadenylation sequence (4). At late times, this block in elongation is alleviated and transcripts initiated at the MLP continue to the right hand end of the genome. The control of MLTU transcription is further regulated by events taking place at the level of poly(A) and alternative 3Ј splice site selection (2, 5, 6). Thus, although nuclear transcription proceeds across at least the L1, L2 and L3 poly(A) sites a...

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Section: Discussionmentioning

confidence: 54%

L4-33K, an Adenovirus-encoded Alternative RNA Splicing Factor

Törmänen¹,

Backström²,

Carlsson

et al. 2006

Journal of Biological Chemistry

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“…Its contribution involves down-regulation of expression of cellular and early viral genes (1)(2)(3)(4)(5), induction of alternative splicing of viral mRNAs (6,7), and regulation of protein translation through an interaction with the mTOR pathway (8). When expressed outside the context of viral infection, E4orf4 induces nonclassical apoptosis that is caspase-independent in many cell lines and which is preceded by G 2 /M arrest (9 -11).…”

mentioning

confidence: 99%

“…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%

“…PP2A is a major E4orf4 partner, and its interaction with E4orf4 was shown to contribute to all E4orf4 functions known to date (1,6,8,12,16,21). PP2A is composed of three subunits: the catalytic C subunit, a scaffolding A subunit, and one of several regulatory B subunits encoded by at least four unrelated gene families, PR55/B55/B, PR61/B56/BЈ, BЉ, and Bٞ (22), which dictate substrate specificity of the PP2A holoenzyme.…”

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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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“…Thus, by dephosphorylating inhibitory SR proteins, E4orf4 activates the process of mRNA splicing. 90,91 It is not currently known whether these molecules are the direct targets of the E4orf4-PP2A complex and/or whether these molecules play a role in E4orf4 mediated cell death.…”

Section: E4orf4 -Another Tumor-selective Killermentioning

confidence: 99%

Anaphase-Promoting Complex

Encyclopedia of Cancer

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The adenovirus E4-ORF4 splicing enhancer protein interacts with a subset of phosphorylated SR proteins

Cited by 86 publications

References 46 publications

L4-33K, an Adenovirus-encoded Alternative RNA Splicing Factor

L4-33K, an Adenovirus-encoded Alternative RNA Splicing Factor

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

Anaphase-Promoting Complex

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