The Human Adenovirus 5 L4 Promoter Is Activated by Cellular Stress Response Protein p53

Wright, Jordan; Leppard, Keith N.

doi:10.1128/jvi.01924-13

Cited by 13 publications

(24 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, in Ad‐infected normal fibroblasts, the total pool of p53 is not completely degraded, since low levels of the protein are still detectable at very late times postinfection (40 hpi) . The E1B‐dependent association of p53 to adenovirus RC and the finding that p53 activates transcription of the L4 promoter suggests p53 is co‐opted in RC. In addition, E1B stimulates SUMOylation of p53 in the PML‐NB and functions as an E3 SUMO‐1 ligase for this cellular protein, which correlates with the nuclear relocalization and maximal transcriptional repression of p53 in in vitro assays ; however, whether E1B represses transcription activation by p53 in infected cells remains to be determined.…”

Section: Roles Of E1b 55k During Productive Viral Replicationmentioning

confidence: 99%

The biology of the adenovirus E1B 55K protein

Hidalgo

Dobner

et al. 2019

FEBS Letters

View full text Add to dashboard Cite

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...

show abstract

Section: Roles Of E1b 55k During Productive Viral Replicationmentioning

confidence: 99%

The biology of the adenovirus E1B 55K protein

Hidalgo

Dobner

et al. 2019

FEBS Letters

View full text Add to dashboard Cite

show abstract

“…Exogenous expression of the Ad5 E1A, IVa2, and E4 Orf3 proteins was shown to induce L4P activity in luciferase reporter plasmid assays ( 16 ). The cellular tumor suppressor p53 has also been identified as a positive regulator of the L4P, and its depletion is inhibitory to both virus late gene expression and the activity of an L4P reporter plasmid ( 17 ). Furthermore, endogenous p53 has been found to associate with the L4P around the time of its peak activity during the course of a lytic Ad5 infection ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

The Human Adenovirus Type 5 L4 Promoter Is Negatively Regulated by TFII-I and L4-33K

Wright¹,

Atwan²,

Morris³

et al. 2015

J Virol

Self Cite

View full text Add to dashboard Cite

The late phase of adenovirus gene expression is controlled by proteins made in the intermediate phase, including L4 proteins of 22,000- and 33,000-Da apparent molecular mass (L4-22K and -33K proteins) that are expressed initially from the L4 promoter (L4P). The L4P is activated by a combination of viral proteins and cellular p53 and is ultimately inhibited again by its own products. Here, we have examined the L4P of human adenovirus type 5 in detail and have defined its transcription start site, which our data suggest is positioned by a weak TATA box. Rather than contributing positively to promoter activity, a putative initiator element at the transcription start site acts as a target for negative regulation imposed on the L4P by cellular TFII-I. We show that this TFII-I inhibition is relieved by one of the previously defined viral activators of the L4P, the E4 Orf3 protein, which alters the pool of TFII-I in the cell. We also explore further the negative regulation of the L4P by its products and show that the L4-33K protein is more significant in this process than L4-22K. It is the combined actions of positive and negative factors that lead to the transient activation of the L4P at the onset of the late phase of adenovirus gene expression. IMPORTANCE The adenovirus replication cycle proceeds through multiple phases of gene expression in which a key step is the activation of late-phase gene expression to produce proteins from which progeny particles can be formed. Working with human adenovirus type 5, we showed previously that two proteins expressed from the L4 region of the viral genome perform essential roles in moving the infection on into the late phase; these two proteins are produced by the action of a dedicated promoter, the L4P, and without them the infection does not proceed successfully to progeny generation. In this new work, we delineate further aspects of L4P activity and regulation. Understanding how the L4P works, and how it contributes to activation of the late phase of infection, is important to our understanding of natural infections by the virus, in which late gene expression can fail to occur, allowing the virus to persist.

show abstract

“…While this last site was previously predicted to lead to the expression of a small 42 amino acid ORF [53], we propose that this transcript instead primarily encodes for pVIII with a small upstream ORF, as it is over five times as abundant as the canonical pVIII spliced RNA. It should be noted that we did not detect the presence of a putative L4 intermediate promoter TSS at either 12 or 24 hpi [45,77,78]. One hypothesis is that the sequence detected in L4-100K that is necessary for early expression of L4-22K and L4-33K might instead encode for a cis -regulatory element that mediates the early accumulation of these two products produced from the major late promoter.…”

Section: Discussionmentioning

confidence: 96%

Novel splicing and open reading frames revealed by long-read direct RNA sequencing of adenovirus transcripts

Hayer²,

Depledge

et al. 2019

Preprint

View full text Add to dashboard Cite

20Adenovirus is a common human pathogen that relies on host cell processes for production 21 and processing of viral RNA. Although adenoviral promoters, splice junctions, and cleavage and 22 proteins by linking separate gene transcription units. Our work highlights how long-read 33 sequencing technologies can reveal further complexity within viral transcriptomes. : bioRxiv preprint another multifunctional protein that can cooperate with E1A to alter cellular gene expression 61 downstream of p53 as well as form the targeting component of a viral ubiquitin ligase [18][19][20][21][22][23]. 62The remaining early transcription units are all transcriptionally activated by E1A and encode for 63 products of related function. The E2 region on the reverse strand of the AdV genome has both an 64 early and a late promoter, as well as two distinct polyadenylation sites, leading to upstream E2A 65 and downstream E2B transcripts [24]. E2A encodes for the viral DNA-binding protein (DBP), while 66 alternative splicing to E2B encodes for the protein-priming terminal protein (pTP) as well as the 67AdV DNA polymerase (AdPol) [25][26][27]. The E3 region encoded on the top strand also has two 68

show abstract

The Human Adenovirus 5 L4 Promoter Is Activated by Cellular Stress Response Protein p53

Cited by 13 publications

References 42 publications

The biology of the adenovirus E1B 55K protein

The biology of the adenovirus E1B 55K protein

The Human Adenovirus Type 5 L4 Promoter Is Negatively Regulated by TFII-I and L4-33K

Novel splicing and open reading frames revealed by long-read direct RNA sequencing of adenovirus transcripts

Contact Info

Product

Resources

About