Identification and characterization of multiple conserved nuclear localization signals within adenovirus E1A

Marshall, Kris; Cohen, Michael J.; Fonseca, Greg J.; Todorović, Biljana; King, Cason R.; Yousef, Ahmed F.; Zhang, Zhiying; Mymryk, Joe S.

doi:10.1016/j.virol.2014.02.020

Cited by 16 publications

(15 citation statements)

References 34 publications

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“…Even with having substantial differences in primary sequence, E1A proteins are often remarkably consistent in their functional similarities (33). Our findings establish that 5 representative members of the 7 species of HAdV express E1A proteins that make protein-protein interactions with PKA.…”

Section: Discussionmentioning

confidence: 52%

Mimicry of Cellular A Kinase-Anchoring Proteins Is a Conserved and Critical Function of E1A across Various Human Adenovirus Species

King

Gameiro

Tessier

et al. 2018

J Virol

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The E1A proteins of the various human adenovirus (HAdV) species perform the critical task of converting an infected cell into a setting primed for virus replication. While E1A proteins differ in both sequence and mechanism, the evolutionary pressure on viruses with limited coding capacity ensures that these proteins often have significant overlap in critical functions. HAdV-5 E1A is known to use mimicry to rewire cyclic AMP (cAMP) signaling by decoupling protein kinase A (PKA) from cellular A kinase-anchoring proteins (AKAPs) and utilizing PKA to its own advantage. We show here that E1As from other species of HAdV also possess this viral AKAP (vAKAP) function and examine how they manipulate PKA. E1A from most species of HAdV examined contain a small AKAP-like motif in their N terminus which targets the docking-dimerization domain of PKA as the binding interface for a conserved protein-protein interaction. This motif is also responsible for an E1A-mediated relocalization of PKA regulatory subunits from the cytoplasm into the nucleus, with species-specific E1A proteins having preference for one particular isoform of PKA subunit over another. Importantly, we showed that these newly characterized vAKAPs can integrate into cAMP-responsive transcription as well as contribute to viral genome replication and infectious progeny production for several distinct HAdV species. These data enhance the mechanistic knowledge on how HAdV E1A manipulates cellular PKA to benefit infection. The work establishes that mimicry of AKAPs and subversion of PKA-mediated cAMP signaling are conserved features for numerous human adenoviruses. This study also highlights the molecular determinants conferring selective protein-protein interactions between distinct PKA regulatory subunits and the different E1A proteins of these viruses. Additionally, it further emphasizes the utility of using viral proteins like E1A as tools for studying the molecular biology of cellular regulatory pathways.

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Section: Discussionmentioning

confidence: 52%

Mimicry of Cellular A Kinase-Anchoring Proteins Is a Conserved and Critical Function of E1A across Various Human Adenovirus Species

King

Gameiro

Tessier

et al. 2018

J Virol

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“…E1A has previously been reported to contain a second nuclear localization signal (NLS) within the first exon of the gene [29]. We therefore wanted to determine whether deletions within this exon affect the sub-cellular localization of E1A while its strong C-terminal NLS remains intact during viral infection.…”

Section: Deletions Within Exon 1 Of E1a Do Not Affect Its Sub-cellulamentioning

confidence: 99%

Characterization of Adenovirus 5 E1A Exon 1 Deletion Mutants in the Viral Replicative Cycle

Costa

Akkerman

Graves

et al. 2020

Viruses

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Human adenovirus infection is driven by Early region 1A (E1A) proteins, which are the first proteins expressed following the delivery of the viral genome to the cellular nucleus. E1A is responsible for reprogramming the infected cell to support virus replication alongside the activation of expression of all viral transcriptional units during the course of the infection. Although E1A has been extensively studied, most of these studies have focused on understanding the conserved region functions outside of a full infection. Here, we investigated the effects of small deletions in E1A exon 1 on the viral replicative cycle. Almost all deletions were found to have a negative impact on viral replication with the exception of one deletion found in the mutant dl1106, which replicated better than the wild-type E1A expressing dl309. In addition to growth, we assessed the virus mutants for genome replication, induction of the cytopathic effect, gene and protein expression, sub-cellular localization of E1A mutant proteins, induction of cellular S-phase, and activation of S-phase specific cellular genes. Importantly, our study found that virus replication is likely limited by host-specific factors, rather than specific viral aspects such as the ability to replicate genomes or express late proteins, after a certain level of these has been expressed. Furthermore, we show that mutants outside of the conserved regions have significant influence on viral fitness. Overall, our study is the first comprehensive evaluation of the dl1100 series of exon 1 E1A deletion mutants in viral fitness and provides important insights into the contribution that E1A makes to viral replication in normal human cells.

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“…Several studies have found that alterations in protein localization can affect cell function (16,17). The occurrence of tumors may be associated with the abnormal localization of proteins; therefore, it was hypothesized that alterations in protein location were also implicated in the pathogenesis of APL.…”

Section: Discussionmentioning

confidence: 99%

NLS-RARα modulates acute promyelocytic leukemia NB4 cell proliferation and differentiation via the PI3K/AKT pathway

Song

Liu

et al. 2016

Molecular Medicine Reports

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In patients with acute promyelocytic leukemia (APL), ~98% express the promyelocytic leukemia (PML)-retinoic acid receptor α (RARα) fusion protein. Previous studies have shown that, in primary leukemia cells of patients with APL, the cleavage of PML-RARα by neutrophil elastase is important for its ability to initiate APL. This cleavage separates the nuclear localization signal (NLS) from PML, leading to the formation of a novel protein, NLS-RARα, although its underlying mechanism in APL remains to be fully elucidated. In the present study, the role of NLS-RARα on the proliferation and differentiation of APL NB4 cells was investigated. Lentiviral vectors were constructed and transfected NLS-RARα in NB4 cells, puromycin was used to select the stable transfected cell lines. Cell Counting Kit-8 and flow cytometry analysis revealed that the efficient overexpression of NLS-RARα significantly promoted NB4 cell proliferation and inhibited all-trans retinoic acid-induced cell differentiation. Furthermore, the NLS-RARα protein promoted a significant increase in AKT and glycogen synthase kinase 3β (GSK-3β) phosphorylation. The protein levels of phosphorylated (p) AKT and pGSK-3β were decreased following pretreatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002. These findings suggested that NLS-RARα was an important molecule associated with the occurrence of APL via the PI3K-AKT signaling pathway, and indicated that the NLS-RARα protein may be a novel target for the treatment of APL.

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Identification and characterization of multiple conserved nuclear localization signals within adenovirus E1A

Cited by 16 publications

References 34 publications

Mimicry of Cellular A Kinase-Anchoring Proteins Is a Conserved and Critical Function of E1A across Various Human Adenovirus Species

Mimicry of Cellular A Kinase-Anchoring Proteins Is a Conserved and Critical Function of E1A across Various Human Adenovirus Species

Characterization of Adenovirus 5 E1A Exon 1 Deletion Mutants in the Viral Replicative Cycle

NLS-RARα modulates acute promyelocytic leukemia NB4 cell proliferation and differentiation via the PI3K/AKT pathway

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