The biology of the adenovirus E1B 55K protein

Abstract

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...

The Interplay between Adeno-Associated Virus and Its Helper Viruses

“…The E1B55K protein, on the other hand, binds and inhibits the tumor suppressor protein p53, and therefore promotes cell-cycle progression and inhibits apoptosis [ 173 , 174 , 175 ]. The tightly regulated interplay between the AdV early proteins E1A and E1B represents the core of the AdV oncogenic nature and has been studied intensively (reviewed in [ 173 , 176 , 177 ]). The last important AdV early protein we will discuss here is encoded by E4orf6 .…”

Formation of adenovirus DNA replication compartments

“…The major core protein VII remains associated with the incoming viral DNA and protects the viral genome from cellular components of the DNA damage response (DDR) , participating in the initial inhibition of the cellular antiviral response , before expression of the E1A , E1B , E2, and E4 genes. These early genes encode multifunctional proteins that are at least transiently localized in AdRCs and are known to alter or to regulate many of the molecular processes that take place there (described in the following sections and see also reviews by Hidalgo et al ; Lynch et al ; Sohn S‐Y & Hearing P ; Hidalgo & Gonzalez ; Charman et al in this issue). Shortly after the viral genome has entered the cell nucleus (30 min after infection in HeLa cells), the viral core protein VII and the cellular template‐activating factor I (TAF Iβ) and acidic nuclear phosphoprotein pp32, two subunits of the histone acetyltransferase inhibitor complex, localize at discrete nuclear foci that are thought to regulate viral chromatin formation (see review by Lynch et al in this issue).…”

Near Atomic Structure of an Atadenovirus Reveals a Conserved Capsid-Binding Motif and Intergenera Variations in Cementing Proteins

“…was previously referred to as E1B 55K, due to limited sequence homology with the gene placed in a similar position in the HAdV genome (Vrati et al, 1996). However, HAdV protein E1B 55K is not part of the virion, but is expressed in infected cells where it carries a large variety of functions, including promotion of genome replication and transcription, degradation of antiviral factors, or deregulation of the cell cycle (Hidalgo et al, 2019).…”

“…When atadenoviruses were first characterized, LH3 was considered a homolog for the HAdV E1B 55K protein, because of its location at the left end of the genome and a limited similarity with mastadenovirus E1B 55K sequences (Vrati et al, 1996). However, the discovery that LH3 was present in the virion, unlike E1B 55K which is a multifunctional protein involved in cell control and transformation, shed doubts on the homology (Gorman et al, 2005;Hidalgo et al, 2019). Alignment of the LAdV-2 LH3 and HAdV-C5 E1B 55K sequences shows a modest similarity (11% identity).…”