28 results on '"Sheehy, Noreen"'
Search Results
2. D614G SARS-CoV-2 Pseudovirus Infectivity and Binding of Spike Protein to the ACE2 Receptor Inversely Correlates with Serum SARS-CoV-2-Specific IgG Levels.
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McCullagh, Laura, Sheehy, Noreen, De Gascun, Cillian F., and Hassan, Jaythoon
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SARS-CoV-2 , *CARRIER proteins , *FC receptors , *CELL receptors , *PROTEIN receptors , *IMMUNOGLOBULIN G - Abstract
Understanding the functional characteristics of antibodies produced against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will assist in the determination of disease outcomes for this virus. In this study, the ability of antibodies to inhibit viral entry into the host cell through the interaction of the receptor binding domain of the viral spike protein and the angiotensin-converting enzyme 2 receptor on the human cell surface was investigated. The SARS-CoV-2 IgG levels in 20 SARS-CoV-2 positive patients were measured using an enzyme-linked immunosorbent assay, and the samples were further analyzed using a functional binding assay. Inhibition of viral infectivity was also measured using a pseudovirus neutralization assay against a D614G SARS-CoV-2 virus strain. A significant correlation between IgG levels and neutralizing antibody 50% inhibitory concentration (IC50) titers was observed (p < 0.05). Similarly, the IC50 titers obtained in the neutralization and binding assays were significantly correlated (p < 0.001). Varying levels of IgG and IC50 titers were observed for the SARS-CoV-2 antibody-positive samples, with one sample not showing any neutralizing capability despite detectable IgG levels. Gender comparisons showed no statistical differences in any of the assays. These results suggest that increased SARS-CoV-2 IgG levels correlate with greater protection against the entry of the virus into cells; however, further investigations in larger studies are needed to confirm the correlates of protection. [ABSTRACT FROM AUTHOR]
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- 2023
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3. JC virus in the Irish population: Significant increase of genotype 2 in immunocompromised individuals
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Schaffer, Kirsten, Sheehy, Noreen, Coughlan, Suzie, Bergin, Colm, and Hall, William W.
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- 2006
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4. Stromal cells help ATL cells to escape from apoptosis induced by histone deacetylase inhibitors
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Yoshiki Takashi, Sheehy Noreen, Oliveira André L A, Tomaru Utano, Miyatake Yukiko, Kasahara Masanori, and Hall William W
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2011
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5. Physical and functional interaction between the HTLV-1 Tax oncoprotein and the cellular LIM domain protein FHL3
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Sheehy Noreen, Hall William W, and McCabe Áine
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2011
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6. Regulation of AP-1 activity by the HTLV-2 APH-2 protein
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Sheehy Noreen, Hall William W, and Marban Céline
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2011
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7. Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I
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Hasegawa, Hideki, Sawa, Hirofumi, Lewis, Martha J, Orba, Yasuko, Sheehy, Noreen, Yamamoto, Yoshie, Ichinohe, Takeshi, Tsunetsugu-Yokota, Yasuko, Katano, Harutaka, Takahashi, Hidehiro, Matsuda, Junichiro, Sata, Tetsutaro, Kurata, Takeshi, Nagashima, Kazuo, and Hall, William W
- Abstract
Adult T-cell leukemia-lymphoma (ATLL) is a group of T-cell malignancies caused by infection with human T-lymphotropic virus type I (HTLV-I). Although the pathogenesis of ATLL remains incompletely understood, the viral regulatory protein Tax is centrally involved in cellular transformation. Here we describe the generation of HTLV-I Tax transgenic mice using the Lck proximal promoter to restrict transgene expression to developing thymocytes. After prolonged latency periods, transgenic mice developed diffuse large-cell lymphomas and leukemia with clinical, pathological and immunological features characteristic of acute ATLL. Transgenic mice were functionally immunocompromised and they developed opportunistic infections. Fulminant disease also developed rapidly in SCID mice after engraftment of lymphomatous cells from transgenic mice. Flow cytometry showed that the cells were CD4[sup.-] and CD8[sup.-], but CD44[sup.+], CD25[sup.+] and cytoplasmic CD3[sup.+]. This phenotype is indicative of a thymus-derived pre-T-cell phenotype, and disease development was associated with the constitutive activation of NF-[kappa]B. Our model accurately reproduces human disease and will provide a tool for analysis of the molecular events in transformation and for the development of new therapeutics., Author(s): Hideki Hasegawa [1, 2, 8]; Hirofumi Sawa [3, 4, 8]; Martha J Lewis [2, 5]; Yasuko Orba [3]; Noreen Sheehy [2]; Yoshie Yamamoto [6]; Takeshi Ichinohe [1]; Yasuko Tsunetsugu-Yokota [...]
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- 2006
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8. Direct interaction of the human I-mfa domain-containing protein, HIC, with HIV-1 Tat results in cytoplasmic sequestration and control of Tat activity
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Gautier, Virginie W., Sheehy, Noreen, Duffy, Margaret, Hashimoto, Kenichi, and Hall, William W.
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Human beings -- Physiological aspects ,Human beings -- Research ,Man -- Physiological aspects ,Man -- Research ,Proteins -- Research ,Science and technology - Abstract
The primary function of the HIV-1 regulatory protein Tat, activation of transcription from the viral LTR, is highly regulated by complex interactions between Tat and a number of host cell proteins. Tat nuclear import, a process mediated by importin [beta], is a prerequisite for its activity. Here, we report and characterize the interaction of the human inhibitor of MyoD family domain-containing protein (I-mfa), HIC, with Tat at a biochemical and a functional level. This interaction was shown to occur in vivo and in vitro and to involve the nuclear localization signal and the transactivation responsive element-binding domains of Tat and the I-tufa domain of HIC. Coexpression of HIC and Tat resulted in the down-regulation of transactivation of the HIV-1 LTR, and colocalization studies revealed the cytoplasmic sequestration of Tat by HIC. Functionally this sequestration appears to be the underlying mechanism of LTR transcriptional repression by HIC and represents a unique mechanism for the control of Tat activity and regulation of HIV-1 replication. NLS | protein-protein interaction | nuclear import
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- 2005
9. In vitro nuclear interactome of the HIV-1 Tat protein
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Hall William W, Sheehy Noreen, Pennington Stephen, O'Donoghue Niaobh, Gu Lili, and Gautier Virginie W
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2009
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10. Interplay between the HTLV-2 Tax and APH-2 proteins in the regulation of the AP-1 pathway
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Marban Céline, McCabe Áine, Bukong Terence N, Hall William W, and Sheehy Noreen
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HTLV-2 ,APH-2 ,Tax2 ,AP-1 ,Jun ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Background In contrast with human T-cell leukemia virus type 1 (HTLV-1) that causes ATL (adult T-cell leukemia), HTLV-2 has not been causally linked to malignant disease. The minus strand of the HTLV genomes encode the regulatory proteins HTLV-1 bZIP factor (HBZ) for HTLV-1 and antisense protein of HTLV-2 (APH-2) for HTLV-2. Unlike the viral proteins Tax1 and Tax2, both HBZ and APH-2 are constitutively expressed in infected cells suggesting that they may play important roles in the pathogenesis of these viruses. To date, very little is known about the function of APH-2 except that it inhibits Tax2-mediated transcription of HTLV-2 genes. In the present study, we investigated the role of APH-2 in basal and Tax2B-mediated activation of the AP-1 pathway. Results We demonstrate that, unlike HBZ, APH-2 stimulates basal AP-1 transcription by interacting with c-Jun and JunB through its non-conventional bZIP domain. In addition, when Tax2 and APH-2 are co-expressed, they physically interact in vivo and in vitro and APH-2 acts as an inhibitor of Tax2-mediated activation of AP-1 transcription. Conclusions This report is the first to document that HTLV-2 can modulate the AP-1 pathway. Altogether our results reveal that, in contrast with HBZ, APH-2 regulates AP-1 activity in a Tax2-dependant manner. As the AP-1 pathway is involved in numerous cellular functions susceptible to affect the life cycle of the virus, these distinct biological properties between HBZ and APH-2 may contribute to the differential pathogenic potential of HTLV-1 and HTLV-2.
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- 2012
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11. Intermolecular masking of the HIV-1 Rev NLS by the cellular protein HIC: Novel insights into the regulation of Rev nuclear import
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Sheehy Noreen, Yeo Geok P, Jarboui Mohamed, Tsuji Takahiro, Gu Lili, Hall William W, and Gautier Virginie W
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Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Background The HIV-1 regulatory protein Rev, which is essential for viral replication, mediates the nuclear export of unspliced viral transcripts. Rev nuclear function requires active nucleocytoplasmic shuttling, and Rev nuclear import is mediated by the recognition of its Nuclear Localisation Signal (NLS) by multiple import factors, which include transportin and importin β. However, it remains unclear which nuclear import pathway(s) predominate in vivo, and the cellular environment that modulates Rev nucleocytoplasmic shuttling remains to be characterised. Results In our study, we have identified the cellular protein HIC (Human I-mfa domain-Containing protein) as a novel interactor of HIV-1 Rev. We demonstrate that HIC selectively interferes with Rev NLS interaction with importin β and impedes its nuclear import and function, but does not affect Rev nuclear import mediated by transportin. Hence, the molecular determinants mediating Rev-NLS recognition by importin β and transportin appear to be distinct. Furthermore, we have employed HIC and M9 M, a peptide specifically designed to inhibit the transportin-mediated nuclear import pathway, to characterise Rev nuclear import pathways within different cellular environments. Remarkably, we could show that in 293T, HeLa, COS7, Jurkat, U937, THP-1 and CEM cells, Rev nuclear import is cell type specific and alternatively mediated by transportin or importin β, in a mutually exclusive fashion. Conclusions Rev cytoplasmic sequestration by HIC may represent a novel mechanism for the control of Rev function. These studies highlight that the multivalent nature of the Rev NLS for different import receptors enables Rev to adapt its nuclear trafficking strategy.
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- 2011
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12. Comparison of CREB- and NF-κB-Mediated Transactivation by Human T Lymphotropic Virus Type II (HTLV-II) and Type I (HTLV-I) Tax Proteins
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Lewis, Martha J., Sheehy, Noreen, Salemi, Marco, VanDamme, Anne-Mieke, and Hall, William W.
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- 2002
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13. Comparative Rates of Nucleotide Sequence Variation in the Hypervariable Region of E1/E2 and the NS5b Region of Hepatitis C Virus in Patients with a Spectrum of Liver Disease Resulting from a Common Source of Infection
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Duffy, Margaret, Salemi, Marco, Sheehy, Noreen, Vandamme, Anne-Mieke, Hegarty, John, Curry, Michael, Nolan, Niamh, Kelleher, Dermot, McKiernan, Susan, and Hall, William W.
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- 2002
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14. In vitro nuclear interactome of the HIV-1 Tat protein
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Gautier Virginie W, Gu Lili, O'Donoghue Niaobh, Pennington Stephen, Sheehy Noreen, and Hall William W
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Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Background One facet of the complexity underlying the biology of HIV-1 resides not only in its limited number of viral proteins, but in the extensive repertoire of cellular proteins they interact with and their higher-order assembly. HIV-1 encodes the regulatory protein Tat (86–101aa), which is essential for HIV-1 replication and primarily orchestrates HIV-1 provirus transcriptional regulation. Previous studies have demonstrated that Tat function is highly dependent on specific interactions with a range of cellular proteins. However they can only partially account for the intricate molecular mechanisms underlying the dynamics of proviral gene expression. To obtain a comprehensive nuclear interaction map of Tat in T-cells, we have designed a proteomic strategy based on affinity chromatography coupled with mass spectrometry. Results Our approach resulted in the identification of a total of 183 candidates as Tat nuclear partners, 90% of which have not been previously characterised. Subsequently we applied in silico analysis, to validate and characterise our dataset which revealed that the Tat nuclear interactome exhibits unique signature(s). First, motif composition analysis highlighted that our dataset is enriched for domains mediating protein, RNA and DNA interactions, and helicase and ATPase activities. Secondly, functional classification and network reconstruction clearly depicted Tat as a polyvalent protein adaptor and positioned Tat at the nexus of a densely interconnected interaction network involved in a range of biological processes which included gene expression regulation, RNA biogenesis, chromatin structure, chromosome organisation, DNA replication and nuclear architecture. Conclusion We have completed the in vitro Tat nuclear interactome and have highlighted its modular network properties and particularly those involved in the coordination of gene expression by Tat. Ultimately, the highly specialised set of molecular interactions identified will provide a framework to further advance our understanding of the mechanisms of HIV-1 proviral gene silencing and activation.
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- 2009
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15. Functional analysis of human T lymphotropic virus type 2 Tax proteins
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Gautier Virginie, Lewis Martha, Watters Karen, Lillis Lorraine, Sheehy Noreen, and Hall William
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Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Background The Tax proteins encoded by human T lymphotropic virus type 1 (HTLV-1) and type 2 (HTLV-2) are transcriptional activators of both the viral long terminal repeat (LTR) and cellular promoters via the CREB and NFkB pathways. In contrast to HTLV-1, HTLV-2 has been classified into four distinct genetic subtypes A, B, C and D defined by phylogenetic analysis of their nucleotide sequences and the size and amino acid sequence of their Tax proteins. In the present study we have analysed and compared the transactivating activities of three Tax 2A and one Tax 2B proteins using LTR and NFkB reporter assays. Results We found that with the exception of the prototype Tax 2A Mo protein, the other two Tax 2A proteins failed to transactivate either the viral LTR or NFkB promoter in Jurkat and 293T cells. Loss of activity was not associated with either expression levels or an alteration in subcellular distribution as all Tax 2 proteins were predominantly located in the cytoplasm of transfected cells. Analysis of the sequence of the two inactive Tax 2A proteins relative to Mo indicated that one had six amino acid changes and the other had one change in the central region of the protein. Mutations present at the amino and the extreme carboxy termini of Mo resulted in the loss of LTR but not NFkB activation whereas those occurring in the central region of the protein appeared to abolish transactivation of both promoters. Analysis of the transactivation phenotypes of Tax 1, Tax 2A Mo and Tax 2B containing mutations identified in the present study or previously characterised Tax mutations showed that domains required for LTR and NFkB activation are very similar but not identical in all three Tax proteins. Conclusion Our results suggest that loss of activity of two Tax 2A proteins derived from different isolates is associated with multiple amino acid changes relative to Mo in domains required for the activation of the CREB or CREB and NFkB pathways and that these domains are very similar but not identical in Tax 2B and Tax 1. The loss of Tax function in 2A viruses may have implications for their biological and pathogenic properties.
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- 2006
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16. Intermolecular masking of the HIV-1 Rev NLS by the cellular protein HIC: Novel insights into the regulation of Rev nuclear import.
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Lili Gu, Tsuji, Takahiro, Jarboui, Mohamed Ali, Yeo, Geok P., Sheehy, Noreen, Hall, William W., and Gautier, Virginie W.
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HIV infections ,VIRAL replication ,NUCLEAR nonproliferation ,HIV ,PEPTIDES - Abstract
Background: The HIV-1 regulatory protein Rev, which is essential for viral replication, mediates the nuclear export of unspliced viral transcripts. Rev nuclear function requires active nucleocytoplasmic shuttling, and Rev nuclear import is mediated by the recognition of its Nuclear Localisation Signal (NLS) by multiple import factors, which include transportin and importin β. However, it remains unclear which nuclear import pathway(s) predominate in vivo, and the cellular environment that modulates Rev nucleocytoplasmic shuttling remains to be characterised. Results: In our study, we have identified the cellular protein HIC (Human I-mfa domain-Containing protein) as a novel interactor of HIV-1 Rev. We demonstrate that HIC selectively interferes with Rev NLS interaction with importin β and impedes its nuclear import and function, but does not affect Rev nuclear import mediated by transportin. Hence, the molecular determinants mediating Rev-NLS recognition by importin β and transportin appear to be distinct. Furthermore, we have employed HIC and M9 M, a peptide specifically designed to inhibit the transportinmediated nuclear import pathway, to characterise Rev nuclear import pathways within different cellular environments. Remarkably, we could show that in 293T, HeLa, COS7, Jurkat, U937, THP-1 and CEM cells, Rev nuclear import is cell type specific and alternatively mediated by transportin or importin β, in a mutually exclusive fashion. Conclusions: Rev cytoplasmic sequestration by HIC may represent a novel mechanism for the control of Rev function. These studies highlight that the multivalent nature of the Rev NLS for different import receptors enables Rev to adapt its nuclear trafficking strategy. [ABSTRACT FROM AUTHOR]
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- 2011
- Full Text
- View/download PDF
17. The Nuclear Import of the Human T Lymphotropic Virus Type I (HTLV-1) Tax Protein Is Carrier- and Energy-independent.
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Tsuji, Takahiro, Sheehy, Noreen, Gautier, Virginie W., Hayakawa, Hitoshi, Sawa, Hirofumi, and Hall, William W.
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T cells , *VIRUSES , *LEUKEMIA etiology , *LYMPHOMAS , *GENE expression - Abstract
HTLV-1 is the etiologic agent of the adult T cell leukemia-lymphoma (ATLL). The viral regulatory protein Tax plays a central role in leukemogenesis as a transcriptional transactivator of both viral and cellular gene expression, and this requires Tax activity in both the cytoplasm and the nucleus. In the present study, we have investigated the mechanisms involved in the nuclear localization of Tax. Employing a GFP fusion expression system and a range of Tax mutants, we could confirm that the N-terminal 60 amino acids, and specifically residues within the zinc finger motif in this region, are important for nuclear localization. Using an in vitro nuclear import assay, it could be demonstrated that the transportation of Tax to the nucleus required neither energy nor carrier proteins. Specific and direct binding between Tax and p62, a nucleoporin with which the importin beta family of proteins have been known to interact was also observed. The nuclear import activity of wild type Tax and its mutants and their binding affinity for p62 were also clearly correlated, suggesting that the entry of Tax into the nucleus involves a direct interaction with nucleoporins within the nuclear pore complex (NPC). The nuclear export of Tax was also shown to be carrier independent. It could be also demonstrated that Tax it self may have a carrier function and that the NF-κB subunit p65 could be imported into the nucleus by Tax. These studies suggest that Tax could alter the nucleocytoplasmic distribution of cellular proteins, and this could contribute to the deregulation of cellular processes observed in HTLV-1 infection. [ABSTRACT FROM AUTHOR]
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- 2007
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18. Functional analysis of human T lymphotropic virus type 2 Tax proteins.
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Sheehy, Noreen, Lillis, Lorraine, Watters, Karen, Lewis, Martha, Gautier, Virginie, and Hall, William
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FUNCTIONAL analysis , *T cells , *PHYLOGENY , *NUCLEOTIDE sequence , *CYTOPLASM , *AMINO acids - Abstract
Background: The Tax proteins encoded by human T lymphotropic virus type 1 (HTLV-1) and type 2 (HTLV-2) are transcriptional activators of both the viral long terminal repeat (LTR) and cellular promoters via the CREB and NFkB pathways. In contrast to HTLV-1, HTLV-2 has been classified into four distinct genetic subtypes A, B, C and D defined by phylogenetic analysis of their nucleotide sequences and the size and amino acid sequence of their Tax proteins. In the present study we have analysed and compared the transactivating activities of three Tax 2A and one Tax 2B proteins using LTR and NFkB reporter assays. Results: We found that with the exception of the prototype Tax 2A Mo protein, the other two Tax 2A proteins failed to transactivate either the viral LTR or NFkB promoter in Jurkat and 293T cells. Loss of activity was not associated with either expression levels or an alteration in subcellular distribution as all Tax 2 proteins were predominantly located in the cytoplasm of transfected cells. Analysis of the sequence of the two inactive Tax 2A proteins relative to Mo indicated that one had six amino acid changes and the other had one change in the central region of the protein. Mutations present at the amino and the extreme carboxy termini of Mo resulted in the loss of LTR but not NFkB activation whereas those occurring in the central region of the protein appeared to abolish transactivation of both promoters. Analysis of the transactivation phenotypes of Tax 1, Tax 2A Mo and Tax 2B containing mutations identified in the present study or previously characterised Tax mutations showed that domains required for LTR and NFkB activation are very similar but not identical in all three Tax proteins. Conclusion: Our results suggest that loss of activity of two Tax 2A proteins derived from different isolates is associated with multiple amino acid changes relative to Mo in domains required for the activation of the CREB or CREB and NFkB pathways and that these domains are very similar but not identical in Tax 2B and Tax 1. The loss of Tax function in 2A viruses may have implications for their biological and pathogenic properties. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
19. Direct interaction of the human I-mfa domaincontaining protein, HIC, with HIV-1 Tat results in cytoplasmic sequestration and control of Tat activity.
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Gautier, Virginie W., Sheehy, Noreen, Duffy, Margaret, Hashimoto, Kenichi, and Hall, William W.
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GENETIC transcription , *PROTEINS , *GENETIC code , *SEQUESTRATION (Chemistry) , *BIOMOLECULES , *GENETICS - Abstract
The primary function of the HIV-1 regulatory protein Tat, activation of transcription from the viral LTR, is highly regulated by complex interactions between Tat and a number of host cell proteins. Tat nuclear import, a process mediated by importin β, is a prerequisite for its activity. Here, we report and characterize the interaction of the human inhibitor of MyoD family domain-containing protein (l-mfa), HIC, with Tat at a biochemical and a functional level. This interaction was shown to occur in vivo and in vitro and to involve the nuclear localization signal and the transactivation responsive element-binding domains of Tat and the I-mfa domain of HIC. Coexpression of HIC and Tat resulted in the down-regulation of transactivation of the HIV-1 LTR, and colocalization studies revealed the cytoplasmic sequestration of Tat by HIC. Functionally this sequestration appears to be the underlying mechanism of LTR transcriptional repression by HIC and represents a unique mechanism for the control of Tat activity and regulation of HIV-1 replication. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
20. Analysis of partial 16S rRNA nucleotide sequences of Chlamydia pecorum and C. psittaci.
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Sheehy, Noreen, Markey, Bryan, and Quinn, P.Joseph
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- 1997
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21. 115 HIV-1 Rev and Regulation of Rev Nucleo-Cytoplasmic Shuttling.
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Hall, William W, Gu, Lili, Sheehy, Noreen, and Gautier, Virginie
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- 2011
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22. The ESCRT-0 Protein HRS Interacts with the Human T Cell Leukemia Virus Type 2 Antisense Protein APH-2 and Suppresses Viral Replication.
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Martini, Fanny, Arone, Coline, Hasset, Amy, Hall, William W., and Sheehy, Noreen
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HTLV , *ANTISENSE peptides , *LYSOSOMES , *BOVINE viral diarrhea , *VIRAL replication - Abstract
The divergent clinical outcomes of human T cell leukemia virus type 1 (HTLV-1) and HTLV-2 infections have been attributed to functional differences in their antisense proteins. In contrast to HTLV-1 bZIP factor (HBZ), the role of the antisense protein of HTLV-2 (APH-2) in HTLV-2 infection is poorly understood. In previous studies, we identified the endosomal sorting complex required for transport 0 (ESCRT-0) subunit HRS as a novel interaction partner of APH-2 but not HBZ. HRS is a master regulator of endosomal protein sorting for lysosomal degradation and is hijacked by many viruses to promote replication. However, no studies to date have shown a link between HTLVs and HRS. In this study, we sought to characterize the interaction between HRS and APH-2 and to investigate the impact of HRS on the life cycle of HTLV-2. We confirmed a direct specific interaction between APH-2 and HRS and showed that the CC2 domain of HRS and the N-terminal domain of APH-2 mediate their interaction. We demonstrated that HRS recruits APH-2 to early endosomes, possibly furnishing an entry route into the endosomal/lysosomal pathway. We demonstrated that inhibition of this pathway using either bafilomycin or HRS overexpression substantially extends the half-life of APH-2 and stabilizes Tax2B expression levels. We found that HRS enhances Tax2B-mediated long terminal repeat (LTR) activation, while depletion of HRS enhances HTLV-2 production and release, indicating that HRS may have a negative impact on HTLV-2 replication. Overall, our study provides important new insights into the role of the ESCRT-0 HRS protein, and by extension the ESCRT machinery and the endosomal/lysosomal pathway, in HTLV-2 infection. [ABSTRACT FROM AUTHOR]
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- 2020
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23. Novel Interactions between the Human T-Cell Leukemia Virus Type 1 Antisense Protein HBZ and the SWI/SNF Chromatin Remodeling Family: Implications for Viral Life Cycle.
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Alasiri, Ahlam, Guerr, Jorge Abboud, Hall, William W., and Sheehy, Noreen
- Subjects
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HTLV-I , *ANTISENSE peptides , *VIRAL proteins , *ADULT T-cell leukemia , *CHROMATIN , *PROTEIN domains , *HISTONES - Abstract
The human T-cell leukemia virus type 1 (HTLV-1) regulatory proteins Tax and HBZ play indispensable roles in regulating viral and cellular gene expression. BRG1, the ATPase subunit of the SWI/SNF chromatin remodeling complex, has been demonstrated to be essential not only for Tax transactivation but also for viral replication. We sought to investigate the physical interaction between HBZ and BRG1 and to determine the effect of these interactions on Tax-mediated long terminal repeat (LTR) activation. We reveal that HTLV-1 cell lines and adult T-cell leukemia (ATL) cells harbor high levels of BRG1. Using glutathione S-transferase (GST) pulldown and coimmunoprecipitation assays, we have demonstrated physical interactions between BRG1 and HBZ and characterized the protein domains involved. Moreover, we have identified the PBAF signature subunits BAF200 and BAF180 as novel interaction partners of HBZ, suggesting that the PBAF complex may be required for HTLV-1 transcriptional repression by HBZ. Additionally, we found that BRG1 expression translocates HBZ into distinct nuclear foci. We show that HBZ substantially represses HTLV-1 LTR activation by Tax/BRG1. Interestingly, we found that Tax stabilizes the expression of exogenous and endogenous BRG1 and that HBZ reverses this effect. Finally, using a chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) assay, we illustrate that HBZ facilitates the downregulation of HTLV-1 transcription by deregulating the recruitment of SWI/SNF complexes to the promoter. Overall, we conclude that SWI/SNF complexes, in addition to other cellular transcription factors, are involved in HBZ-mediated suppression of HTLV-1 viral gene expression. IMPORTANCE The pathogenic potential of HTLV-1 is linked to the indispensable multifaceted functions of the viral regulatory proteins Tax and HBZ, encoded by the sense and antisense viral transcripts, respectively. The interaction between Tax and the SWI/SNF family of chromatin remodeling complexes has been associated with HTLV-1 transcriptional activation. To date, the relationship between the SWI/SNF chromatin remodeling family and HBZ, the only viral protein that is consistently expressed in infected cells and ATL cells, has not been elucidated. Here, we have characterized the biological significance of the SWI/SNF family in regard to viral transcriptional repression by HBZ. This is important because it provides a better understanding of the function and role of HBZ in downregulating viral transcription and, hence, its contribution to viral latency and persistence in vivo, a process that may ultimately lead to the development of ATL. [ABSTRACT FROM AUTHOR]
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- 2019
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24. Positive and Negative Regulation of Type I Interferons by the Human T Cell Leukemia Virus Antisense Protein HBZ.
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Narulla, Manraj Singh, Alsairi, Ahlam, Charmier, Lucie, Noonan, Stephen, Conroy, David, Hall, William W., and Sheehy, Noreen
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TYPE I interferons , *HTLV , *ANTISENSE peptides , *NATURAL immunity , *PARAPARESIS - Abstract
The pathogenesis of human T cell leukemia virus type 1 (HTLV-1) is strongly linked to the viral regulatory proteins Tax1 and HBZ, whose opposing functions contribute to the clinical outcome of infection. Type I interferons alpha and beta (IFN-α and IFN-β) are key cytokines involved in innate immunity, and IFN-α, in combination with other antivirals, is extensively used in the treatment of HTLV-1 infection. The relationship between HTLV-1 and IFN signaling is unclear, and to date the effect of HBZ on this pathway has not been examined. Here we report that HBZ significantly enhances interferon regulatory factor 7 (IRF7)-induced IFN-α- and IFNstimulated response element (ISRE) promoter activities and IFN-α production and can counteract the inhibitory effect of Tax1. In contrast to this, we show that HBZ and Tax1 cooperate to inhibit the induction of IFN-β and ISRE promoters by IRF3 and IFN-β production. In addition, we reveal that HBZ enhances ISRE activation by IFN-α. We further show that HBZ enhances IRF7 and suppresses IRF3 activation by TBK1 and IKK+. We demonstrate that HBZ has no effect on virus-induced nuclear accumulation of IRF3, suggesting that it may inhibit IRF3 activity at a transcriptional level. We show that HBZ physically interacts with IRF7 and IKK but not with IRF3 or TBK1. Overall, our findings suggest that both HBZ and Tax1 are negative regulators of immediate early IFN-β innate immune responses, while HBZ but not Tax1 positively regulates the induction of IFN-α and downstream IFN-α signaling. [ABSTRACT FROM AUTHOR]
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- 2017
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25. Novel interactions between the HTLV antisense proteins HBZ and APH-2 and the NFAR protein family: Implications for the HTLV lifecycles
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Sheehy, Noreen [Centre for Research in Infectious Diseases, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4 (Ireland)]
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- 2016
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26. Novel interactions between the HTLV antisense proteins HBZ and APH-2 and the NFAR protein family: Implications for the HTLV lifecycles.
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Murphy, Jane, Hall, William W., Ratner, Lee, and Sheehy, Noreen
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HTLV-I , *PROTEIN kinases , *VIRUS diseases , *IMMUNOLOGY , *NATURAL immunity , *DOUBLE-stranded RNA , *SURVIVIN (Protein) - Abstract
The human T-cell leukaemia virus type 1 and type 2 (HTLV-1/HTLV-2) antisense proteins HBZ and APH-2 play key roles in the HTLV lifecycles and persistence in the host. Nuclear Factors Associated with double-stranded RNA (NFAR) proteins NF90/110 function in the lifecycles of several viruses and participate in host innate immunity against infection and oncogenesis. Using GST pulldown and co-immunoprecipitation assays we demonstrate specific novel interactions between HBZ/APH-2 and NF90/110 and characterised the protein domains involved. Moreover we show that NF90/110 significantly enhance Tax mediated LTR activation, an effect that was abolished by HBZ but enhanced by APH-2. Additionally we found that HBZ and APH-2 modulate the promoter activity of survivin and are capable of antagonising NF110-mediated survivin activation. Thus interactions between HTLV antisense proteins and the NFAR protein family have an overall positive impact on HTLV infection. Hence NFARs may represent potential therapeutic targets in HTLV infected cells. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
27. The Four and a Half LIM Family Members Are Novel Interactants of the Human T-Cell Leukemia Virus Type 1 Tax Oncoprotein.
- Author
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McCabe, Áine, Hashimoto, Kenichi, Hall, William W., and Sheehy, Noreen
- Subjects
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HTLV-I , *VIRAL proteins , *ETIOLOGY of diseases , *CYTOSKELETON , *CANCER invasiveness , *MOLECULAR biology - Abstract
Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia (ATL). The viral regulatory protein Taxi plays a pivotal role in T-cell transformation and ATL development. Previous studies in our laboratory, using the yeast 2-hy-brid approach to screen a T-cell library for Taxi-interacting partners, identified the cellular Four and a Half Lim domain protein 3 (FHL3) as a possible Taxi-interacting candidate. FHL3 is a member of the FHL family of proteins, which function as transcrip-tional coactivators and cytoskeleton regulators and have a role in cancer progression and development. The aim of this study was to investigate the physical and functional interaction between Taxi and members of the FHL family of proteins. We show that Taxi and FHL3 interact both in vitro and in vivo. Furthermore, both FHL1 and -2 also interact with Taxi. We have demon-strated that FHL3 enhances Taxi-mediated activation of the viral long terminal repeat (LTR) without affecting basal activity and that FHL1 to -3 regulate NF-KB activation by Taxi in a cell-specific manner. In addition, we have found that the interaction be-tween Taxi and FHL1 to -3 affects the localization of these proteins, leading to their redistribution in cells. Taxi also affected FHL3 cytoskeleton function by increasing FHL3-mediated cell spreading. Overall, our results suggest that the interaction be-tween Taxi and the FHL family alters both the transactivating activity and the subcellular localization of Taxi and provide new insights into molecular mechanisms that underlie the oncogenic nature of this HTLV-1 protein. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
28. Expression profile and differential regulation of the Human I-mfa domain-Containing protein (HIC) gene in immune cells
- Author
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Gu, Lili, Dean, Jonathan, Oliveira, André L.A., Sheehy, Noreen, Hall, William W., and Gautier, Virginie W.
- Subjects
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GENE expression , *GENETIC regulation , *CELL culture , *CYTOKINES - Abstract
Abstract: The Human I-mfa domain-Containing protein, HIC, is a 246 amino acid protein that functions as a transcriptional regulator. Although the precise function of HIC remains to be clarified, the association of the HIC gene locus with myeloid neoplasms, its interactions with lymphotropic viruses such as EBV, HIV-1 and HTLV-1 and its expression in immune tissues suggest that HIC might have a modulatory role in immune cells. To further characterise the HIC functional relationship with the immune system, we sought to analyse the HIC gene expression profile in immune cells and to determine if immunomodulatory cytokines, such as interleukin (IL)-2, could regulate the expression of HIC mRNA. Relative quantitative real-time RT-PCR revealed that HIC mRNA is highly expressed in PBMCs and in various hematopoietic cell lines. The immunomodulatory cytokine IL-2 up-regulated HIC gene expression in PBMCs, CEM, MT-2 and U937 but markedly reduced HIC gene expression in Raji. Addition of cycloheximide indicated that the IL-2 effects were independent of de novo protein synthesis and that the HIC gene is a direct target of IL-2. Two cell lines (Jurkat and BJAB) displayed a distinct loss in HIC gene expression. However, when these cell lines were subjected to a combination of DNA methyltransferase and histone-deacetylase inhibitors, (5-aza-2-deoxycytidine and trichostatin A, respectively), HIC expression was de-repressed, indicating possible epigenetic control of HIC expression. Overall, our study describes that the immune expression of HIC is cell-specific, dynamic, and identifies the HIC gene as an IL-2 responsive gene. Furthermore, our de-repression studies support the hypothesis that HIC might represent a candidate tumor suppressor gene. Overall, this report provides new insights for a putative role of HIC in the modulation of immune and inflammatory responses and/or hematological malignancies. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
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