RUNX1 Permits E4orf6-Directed Nuclear Localization of the Adenovirus E1B-55K Protein and Associates with Centers of Viral DNA and RNA Synthesis

Marshall, Leslie J.; Moore, Amy C.; Ohki, Masafumi; Kitabayashi, Issay; Patterson, David; Ornelles, David A.

doi:10.1128/jvi.00043-08

Cited by 22 publications

(13 citation statements)

References 90 publications

(97 reference statements)

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“…During the early phase of infection, the E4-ORF3 protein organizes nuclear structures which have been implicated in the inhibition of host defense mechanisms: the redistribution of the Mrell-Rad50-Nbs1 (MRN) complex to prevent a DNA damage response and viral genome concatemerization (3,6,40) and promyelocytic leukemia (PML) nuclear bodies to impair the IFN-induced antiviral response (4,5,43). At the late phase of infection, Ad forms replication centers condensed with viral DNA, viral DNA replication proteins, and various cellular proteins to promote efficient viral DNA replication and late gene transcription (6,21,28). Another late-phase-specific nuclear structure is formed by viral intermediate protein pIX (33).…”

Section: Discussionmentioning

confidence: 99%

Adenovirus Sequesters Phosphorylated STAT1 at Viral Replication Centers and Inhibits STAT Dephosphorylation

Sohn

Hearing

2011

J Virol

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In response to type I IFNs, STAT1 and STAT2 undergo phosphorylation mediated by receptor-associated kinases, Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2), and form the heterotrimeric IFN-stimulated gene factor 3 (ISGF3) complex, together with IFN-regulatory factor 9 (IRF9), followed by nuclear translocation (reviewed in reference 27). The ISGF3 complex binds and activates the ISRE-containing promoters of IFN-inducible genes. After release from promoter regions, STAT1 is dephosphorylated by a nuclear protein tyrosine phosphatase, TC45, and exported to the cytoplasm (23). IFN signal transduction pathways are activated rapidly but persist only transiently in the absence of additional stimulation; aberrant regulation causes various immune disorders. Accurate regulation of STAT1 activity is crucial for the innate immune response, and it is modulated by various posttranslational modifications, such as tyrosine phosphorylation (38), serine phosphorylation (47), methylation (24), sumoylation (45), and ubiquitination (14). In addition, it was recently reported that acetylation of STAT1 causes recruitment of TC45 and subsequent dephosphorylation (16).Several negative regulatory mechanisms for STAT1 activity have also been described. STAT1 can be dephosphorylated by specific phosphatases, such as TC45 (41) and Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP-2) (48). Suppressor of cytokine signaling (SOCS) proteins block STAT1 tyrosine phosphorylation by inactivating kinases through proteasomal degradation (46) and also direct inhibition of tyrosine kinase activity (7). Protein inhibitor of activated STAT (PIAS) proteins prevent DNA binding of STAT1 (19). PIAS family members have been shown to promote STAT1 sumoylation; however, the functional consequences are controversial (32,44,45). These diverse STAT1 regulatory mechanisms can be exploited by viruses to impair IFN signal transduction pathways and, hence, evade host immune response (reviewed in reference 29).STAT1 is a stable protein with a half-life of Ͼ24 h (17). Ad infection has not been reported to affect the basal protein level of STAT1 in unstimulated cells. In a previous study, E1A proteins were shown to interact with STAT1 and inhibit IFN-␥-inducible gene expression in primary human tracheobronchial epithelial (hTBE) cells (20). Using the same cells, these authors also showed that Ad blocks IFN-␣-induced STAT1 tyrosine phosphorylation by downregulating JAK1 expression (37). The E1A proteins were also previously shown to inhibit ISGF3 DNA binding and IFN-stimulated gene expression (1,2,9,13,18,31,35). Ad and other viruses have evolved redundant mechanisms to counteract host antiviral responses. Thus, Ad may have evolved additional strategies to block early stages of an IFN signaling response, since this response is so detrimental to virus infection. This prompted us to investigate if other aspects of Ad infection inhibit IFN-induced antiviral activities.

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Section: Discussionmentioning

confidence: 99%

Adenovirus Sequesters Phosphorylated STAT1 at Viral Replication Centers and Inhibits STAT Dephosphorylation

Sohn

Hearing

2011

J Virol

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“…The nuclear pool of E1B is associated with the viral early protein E4Orf3 colocalizing with the altered distribution of PML‐nuclear bodies (PML‐NB) or with the nuclear matrix, independent from its association with E4Orf3 in infected cells. With progression of the replication cycle, E1B interacts with E4Orf6, an interaction that leads to the localization of the protein at the periphery of viral RC , where the protein promotes proper formation of RC and regulates RC‐associated activities in infected cells.…”

Section: Structural and Functional Features Of E1b 55kmentioning

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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“…At present though, it is not known whether E4orf6 alone is capable of forming oligomers. Moreover, the interaction between E1B-55 kDa and E4orf6 is further complicated by the need for RUNX1 (Marshall et al, 2008). The E4orf6 protein, rather than E1B-55 kDa, is the principal binding partner for cullin 5 and the ubiquitin ligase complex (Querido et al, 2001a;Harada et al, 2002), making it an even more intriguing question whether and how E4orf6 forms higher-order complexes with itself or in association with E1B-55 kDa.…”

Section: Avidity Enables the Interaction Between E1b-55 Kda And P53mentioning

confidence: 99%

Self-association of adenovirus type 5 E1B-55 kDa as well as p53 is essential for their mutual interaction

2009

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The adenovirus type 5 E1B-55 kDa oncoprotein forms a complex with the tumor suppressor p53 and inactivates it. E1B-55 kDa and p53 are each capable of forming oligomers. We mapped the oligomerization domain of E1B-55 kDa to the central portion of the protein. Disturbing E1B-55 kDa self-association by point mutations at residues 285/286 or 307 not only impairs its intracellular localization to the cytoplasmic clusters, but in addition, its association with p53. Strikingly, tetramerization of p53 is also required for efficient association with E1B-55 kDa. Moreover, two different E1B-55 kDa mutants defective for p53 binding but proficient for oligomerization can trans-complement each other for p53 relocalization. We propose that the homo-oligomerization of each component enables efficient interaction between E1B-55 kDa and p53 through increased avidity.

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RUNX1 Permits E4orf6-Directed Nuclear Localization of the Adenovirus E1B-55K Protein and Associates with Centers of Viral DNA and RNA Synthesis

Cited by 22 publications

References 90 publications

Adenovirus Sequesters Phosphorylated STAT1 at Viral Replication Centers and Inhibits STAT Dephosphorylation

Adenovirus Sequesters Phosphorylated STAT1 at Viral Replication Centers and Inhibits STAT Dephosphorylation

The biology of the adenovirus E1B 55K protein

Self-association of adenovirus type 5 E1B-55 kDa as well as p53 is essential for their mutual interaction

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