Sp100A is a tumor suppressor that activates p53-dependent transcription and counteracts E1A/E1B-55K-mediated transformation

Berscheminski, Julia; Brun, Juliane; Speiseder, Thomas; Wimmer, Peter; Ip, Wing Hang; Terzic, M; Dobner, Thomas; Schreiner, Sabrina

doi:10.1038/onc.2015.378

Cited by 16 publications

(16 citation statements)

References 43 publications

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“…Second, the PML‐NB component Sp100A does not activate p53 transcriptional activity upon binding to E1B. This effect is enhanced by E1B‐induced SUMOylation of Sp100A resulting in its relocalization into the nuclear insoluble matrix or into cytoplasmic inclusion bodies . Phosphorylation‐ deficient mutants of E1B showed that the transactivation activity of p53 is only partially inhibited although binding to p53 is comparable to WT E1B .…”

Section: Role Of E1b 55k In Cell Transformationmentioning

confidence: 99%

The biology of the adenovirus E1B 55K protein

Hidalgo

Dobner

et al. 2019

FEBS Letters

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The adenovirus E1B 55K (E1B) protein plays major roles in productive adenoviral infection and cellular transformation. Interest in E1B increased because of the potential of adenoviruses as therapeutic vectors, and the E1B gene is commonly deleted from adenovirus vectors for anticancer therapy. E1B activities are spatiotemporally regulated through SUMOylation and phosphorylation, and through interactions with multiple partners that occur presumably at different intracellular sites and times postinfection. E1B is implicated in the formation of viral replication compartments and regulates viral genome replication and transcription, transcriptional repression, degradation of cellular proteins, and several intranuclear steps of viral late mRNA biogenesis. Here, we review advances in our understanding of E1B during productive adenovirus replication and discuss fundamental aspects that remain unresolved.The adenovirus E1B 55K protein (called E1B throughout this review) plays key roles during productive viral replication and contributes to oncogenic transformation. The E1B gene is usually deleted or modified in oncolytic adenoviruses because such viruses preferentially replicate in and kill cancer cells (reviewed in [1,2]). Although structural data for the 496 amino acid (aa) polypeptide are scarce, some structural or functional motifs are known or have been proposed, and the E1B protein may contain intrinsically disordered regions (IDR). E1B activities are regulated by posttranslational modifications (PTMs) that impact on both intracellular localization and the interactions that E1B establishes with viral and cellular proteins. E1B acts as a small ubiquitin-like modifier (SUMO)-1 ligase for p53 and participates in the polyubiquitylation-induced degradation of cellular targets that would otherwise interfere with viral replication. E1B also promotes viral replication through repression of interferon (IFN)-stimulated genes (ISG) and p53 regulation. Of note, efficient viral DNA replication depends on the formation of adenoviral replication compartments (RCs), another process in which E1B is involved. Furthermore, E1B interacts with viral RNA and this interaction optimizes production and splicing of viral late mRNAs. Yet, many aspects of the biology of E1B remain to be elucidated, including the protein's threedimensional structure and the molecular mechanisms whereby E1B regulates viral genome replication and gene expression. Most of the knowledge of E1B comes from the study of the human serotypes 2 and 5 from species C; however, sequences and functional features from other adenovirus species have also been described. A very complete review of the E1B protein Abbreviations CRM1, chromosome region maintenance 1 protein homolog; CDK, cyclin-dependent kinase; E1B-AP5, E1B-associated protein 5; eIF4E, eukaryotic translation initiation factor 4E; hnRNP, heteronuclear ribonucleoprotein; LH3, hexon-interlacing protein LH3; I-TASSER, iterative threading ASSEmbly refinement; Mre11, meiotic recombination 11; Nxf1/Tap, nuclear RNA expo...

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Section: Role Of E1b 55k In Cell Transformationmentioning

confidence: 99%

The biology of the adenovirus E1B 55K protein

Hidalgo

Dobner

et al. 2019

FEBS Letters

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“…Ubc9 represents the main SUMO-conjugating enzyme also involved in Sp100 SUMOylation (51). Thus, the inability of the E2A SCM to interact with Ubc9 might prevent an HAdV-mediated decrease in Sp100A SUMO moieties and thus block the transcription-activating properties (93). The loss of Sp100A protein levels and faulty PML track/RC cooperation in E2A SCM infection might in sum prevent the virus from exploiting beneficial Sp100A capacity.…”

Section: Discussionmentioning

confidence: 99%

Viral DNA Binding Protein SUMOylation Promotes PML Nuclear Body Localization Next to Viral Replication Centers

Stubbe¹,

Mai²,

Paulus

et al. 2020

mBio

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Human adenoviruses (HAdVs) have developed mechanisms to manipulate cellular antiviral measures to ensure proper DNA replication, with detailed processes far from being understood. Host cells repress incoming viral genomes through a network of transcriptional regulators that normally control cellular homeostasis. The nuclear domains involved are promyelocytic leukemia protein nuclear bodies (PML-NBs), interferon-inducible, dot-like nuclear structures and hot spots of SUMO posttranslational modification (PTM). In HAdV-infected cells, such SUMO factories are found in close proximity to newly established viral replication centers (RCs) marked by the adenoviral DNA binding protein (DBP) E2A. Here, we show that E2A is a novel target of host SUMOylation, leading to PTMs supporting E2A function in promoting productive infection. Our data show that SUMOylated E2A interacts with PML. Decreasing SUMO-E2A protein levels by generating HAdV variants mutated in the three main SUMO conjugation motifs (SCMs) led to lower numbers of viral RCs and PML-NBs, and these two structures were no longer next to each other. Our data further indicate that SUMOylated E2A binds the host transcription factor Sp100A, promoting HAdV gene expression, and represents the molecular bridge between PML tracks and adjacent viral RCs. Consequently, E2A SCM mutations repressed late viral gene expression and progeny production. These data highlight a novel mechanism used by the virus to benefit from host antiviral responses by exploiting the cellular SUMO conjugation machinery. IMPORTANCE PML nuclear bodies (PML-NBs) are implicated in general antiviral defense based on recruiting host restriction factors; however, it is not understood so far why viruses would establish viral replication centers (RCs) juxtaposed to such “antiviral” compartments. To understand this enigma, we investigate the cross talk between PML-NB components and viral RCs to find the missing link connecting both compartments to promote efficient viral replication and gene expression. Taken together, the current concept is more intricate than originally believed, since viruses apparently take advantage of several specific PML-NB-associated proteins to promote productive infection. Simultaneously, they efficiently inhibit antiviral measures to maintain the viral infectious program. Our data provide evidence that SUMOylation of the viral RC marker protein E2A represents the basis of this virus-host interface and regulates various downstream events to support HAdV productive infection. These results are the basis of our current attempts to generate and screen for specific E2A SUMOylation inhibitors to constitute novel therapeutic approaches to limit and prevent HAdV-mediated diseases and mortality of immunosuppressed patients.

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“…Recent evidence demonstrates that the host cell broadly restricts chromatinization of the incoming viral genome during the earliest stages of infection. It is proposed that this restriction occurs via PML-associated proteins Daxx, ATRX, and Sp100 [144][145][146] as well as the chromatin regulator SPOC1 [147]. Outside of viral infection, the Daxx/ATRX histone chaperone complex is thought to promote chromatin silencing via deposition of the H3.3 histone variant.…”

Section: Impact Of E4orf3 On Host Chromatin and Chromatinization Of Vmentioning

confidence: 99%

Epigenetics and the dynamics of chromatin during adenovirus infections

et al. 2019

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Edited by Urs GreberAbbreviations ADP, adenovirus death protein; Ad5 or Ad 12, human adenovirus type 5 or 12, or other type referenced; BHK, baby hamster kidney; BrdU, bromodeoxyuridine; CTCF, CCCTC binding factor; DBS, double stranded break; DDR, DNA damage response; E1A, early 1 A; E4orf3 or E4orf6, early 4 open reading frame 3 or 6; HAdV-A12, human adenovirus subgroup A type 12, or different subgroup or type referenced; HMGB, high-mobility group box; hPaf1, human RNA polymerase II-associated factor 1; ISGs, interferon-stimulated genes; PML, promyelocytic leukemia; snRNP, small nuclear ribonuclear protein; SET or TAF-1, SE translocation or template activating factor; VRCs, viral replication centers.

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Sp100A is a tumor suppressor that activates p53-dependent transcription and counteracts E1A/E1B-55K-mediated transformation

Cited by 16 publications

References 43 publications

The biology of the adenovirus E1B 55K protein

The biology of the adenovirus E1B 55K protein

Viral DNA Binding Protein SUMOylation Promotes PML Nuclear Body Localization Next to Viral Replication Centers

Epigenetics and the dynamics of chromatin during adenovirus infections

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