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            -Acetylglucosaminylation of Sp1 Inhibits the Human Immunodeficiency Virus Type 1 Promoter

Jochmann, Ramona; Thurau, Mathias; Jung, Susan; Hofmann, Christian; Naschberger, Elisabeth; Kremmer, Elisabeth; Harrer, Thomas; Miller, Matthew; Schaft, Niels

doi:10.1128/jvi.01384-08

Cited by 38 publications

(46 citation statements)

References 83 publications

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“…Sp1 is required by HIV-1 for basal transcrip- tion (36) and can target cyclin T1 to the LTR in the absence of Tat or TAR RNA (37). An increase in Sp1 phosphorylation induced by Tat and DNA-PK can enhance HIV-1 transcription (38).…”

Section: Discussionmentioning

confidence: 99%

Expression of a Protein Phosphatase 1 Inhibitor, cdNIPP1, Increases CDK9 Threonine 186 Phosphorylation and Inhibits HIV-1 Transcription

Ammosova

Yedavalli

Niu

et al. 2011

Journal of Biological Chemistry

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Cyclin-dependent kinase-9 (CDK9) 3 /cyclin T1 is a protein kinase that phosphorylates the C-terminal domain of the largest subunit of RNA polymerase II during transcription elongation (1). CDK9/cyclin T1 is part of positive transcription elongation complex (P-TEFb) and present in the cells within large and small complexes. The large complex contains 7SK RNA (2, 3) and the hexamethylene bisacetamide-induced protein (HEXIM1) (4, 5). The activity of CDK9 in the large complex is inhibited by the interaction with 7SK RNA and HEXIM1 (2-5). In stress-induced cells, CDK9/cyclin T1 dissociates from the 7SK RNA and HEXIM1 protein and then binds to the bromodomain protein 4 (Brd4) (6, 7), a member of bromodomain-containing extraterminal domain protein family that interact with acetylated histones. CDK9/cyclin T1 bound to Brd4 forms the transcriptionally active P-TEFb (7). Brd4 recruits P-TEFb to the promoters of cellular genes that are expressed at the end of mitosis (8). HIV-1 Tat protein can also recruit P-TEFb by binding directly to CDK9/cyclin T1 and targeting it to HIV-1 TAR RNA (7). Hence, Tat induces HIV-1 transcription by recruiting CDK9/cyclin T1 (9 -11) and histone acetyltransferases to the HIV-1 promoter (7,(12)(13)(14). The HIV-1 Tat prevents the formation of the large complex and promotes the dissociation of CDK9/cyclin T1 from 7SK RNA/HEXIM1 complex (15). (20) and in cultured cells (21). PP1 holoenzymes consist of a constant catalytic subunit (PP1␣, PP1␤/␦, or PP1␥) and a variable regulatory subunit that determines the localization, activity, and substrate specificity of the phosphatase (22, 23). One of the major nuclear regulators of PP1 is NIPP1 (nuclear inhibitor of PP1), which inhibits the dephosphorylation of a wide range of PP1 substrates (22, 23). Tat-mediated HIV-1 transcription is blocked by the expression of NIPP1, and the inhibition is reversed by the co-expression of PP1␥ (21). Tat contains a PP1-binding The abbreviations used are: CDK9, cyclin-dependent kinase-9; Brd4, bromodomain protein 4; cdNIPP1, central domain NIPP1; EGFP, enhanced green fluorescent protein; HEXIM1, hexamethylene bisacetamide-induced protein; NIPP1, nuclear inhibitor of PP1; P-TEFb, positive transcription elongation complex; PP1, protein phosphatase 1; PP1C, catalytic subunit of PP1; PP2B, protein phosphatase 2B; PPM1A, protein phosphatase M1A; TAR RNA, transactivation response RNA.

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Section: Discussionmentioning

confidence: 99%

Expression of a Protein Phosphatase 1 Inhibitor, cdNIPP1, Increases CDK9 Threonine 186 Phosphorylation and Inhibits HIV-1 Transcription

Ammosova

Yedavalli

Niu

et al. 2011

Journal of Biological Chemistry

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“…The liberated NF-κB then translocates from the cytoplasm to the nucleus and activates the transcription of proinflammatory factors, such as NO, iNOS (4,40). It has been recognized that posttranslational modifications involve the activation of NF-κB, including phosphorylation and acetylation (9,12). O-GlcNAc modifies NF-κB via disrupting its interaction with IκB, which results in translocation of NF-κB into the nuclear and stimulation of NF-κB-dependent gene expression (40,41).…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that O-linked GlcNAcylation and phosphorylation are critical posttranslational modifications (9,12). Many O-GlcNAcylation modified sites are also phosphorylation sites, demonstrating a complex relationship between O-GlcNAcylation and phosphorylation, the so-called 'yin-yang' hypothesis (11,13).…”

Section: Discussionmentioning

confidence: 99%

“…O-Linked O-GlcNAcylation of protein, a single monosaccharide N-acetylglucosamine (GlcNAc) attached to the hydroxyl groups of specific serine or threonine residues, is an important post-translational modification on nuclear and cytoplasmic proteins (9,10). More than 500 proteins have been identified to be O-GlcNAcylated, and these proteins are involved in regulation of cell processes including cell cycle, transcription, trafficking and signaling (11).…”

Section: Introductionmentioning

confidence: 99%

“…A major function of O-GlcNAc may be to antagonize phosphorylation, through competing with phosphorylation for a single site or proximal sites on proteins (9,10,12). Evidence indicated that O-linked GlcNAc modification could modulate many transcription factors, including NF-κB involved in response to stress (9,12,15).…”

Section: Introductionmentioning

confidence: 99%

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Puerarin suppresses production of nitric oxide and inducible nitric oxide synthase in lipopolysaccharide-induced N9 microglial cells through regulating MAPK phosphorylation, O-GlcNAcylation and NF-κB translocation

Zheng

Yu²,

Yang

2012

Int J Oncol

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Abstract. Microglial cells play a critical role in mediating central nervous system inflammatory processes. Activated microglial cells induced by proinflammatory factor, such as lipopolysaccharide (LPS), release many kinds of neurotoxic cytokines including reactive oxygen species (ROS) which contributes to the pathogenesis of neurodegenerative diseases. Puerarin, extracted from kudzu root, possesses the characteristic of neuroprotection, antioxidation and anticancer. In the present study, we observed that LPS induced over-production of nitric oxide (NO) and increased the level of intracellular ROS in N9 microglial cells, but it was inhibited by puerarin. Furthermore, treatment with puerarin on N9 cells suppressed the over-expression of inducible nitric oxide synthase (iNOS) induced by LPS which is implicated in intracellular O-linked β-N-acetylglucosamine (O-GlcNAc) level, phosphorylation of mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathway. We also observed that the enhanced phosphorylation of p38, JNK and ERK1/2 in N9 cells induced by LPS were inhibited by puerarin, otherwise the down-regulation of O-GlcNAcylation level of protein in N9 cell induced by LPS was up-regulated by pretreatment with puerarin. These results indicate that puerarin effectively inhibits microglia activation induced by LPS through inhibiting expression of iNOS, production of NO and ROS which was mediated via regulating O-GlcNAcylation, phosphorylation of MAPK and NF-κB translocation. IntroductionMicroglial cells, macrophage-like cells in the central nervous system, participate in CNS immune response through releasing a variety of factors, including trophic factors and chemokines, to promote neuroprotection (1). Whereas under chronic inflammatory environment, excessive activation of microglia cells secrete cytotoxic substances and neurotoxic cytokines, such as reactive oxygen species (ROS) and nitric oxide (NO) which contribute to the pathogenesis of neurodegenerative diseases (2). Lipopolysaccharide (LPS), which consist in outer membrane of gram-negative bacteria as potent pro-inflammatory agents, induce microglial cell inflammatory injury through releasing proinflammatory mediators such as NO generated by inducible nitric oxide synthase (iNOS) (3,4). NO is considered as a main risk factor of progressive damage in neurodegenerative diseases (5,6). Microglia cell inflammatory response to LPS is involved in speedy regulation of many signal transduction molecules. The regulation of a signal pathway, such as mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB), is implicated in major molecular mechanisms of LPS-induced NO and ROS production in microglial cells (4,(6)(7)(8).O-Linked O-GlcNAcylation of protein, a single monosaccharide N-acetylglucosamine (GlcNAc) attached to the hydroxyl groups of specific serine or threonine residues, is an important post-translational modification on nuclear and cytoplasmic proteins (9,10). More than 500 proteins have been identified to be O-GlcNAcylated...

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Differential transcriptional and functional properties of regulatory T cells in HIV‐infected individuals on antiretroviral therapy and long‐term non‐progressors

2021

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Objectives Regulatory T cells (Tregs) are widely recognised as a subset of CD4+CD25+FOXP3+ T cells that have a key role in maintaining immune homeostasis. The impact of HIV‐1 infection on immunological properties and effector functions of Tregs has remained the topic of debate and controversy. In the present study, we investigated transcriptional profile and functional properties of Tregs in HIV‐1‐infected individuals either receiving antiretroviral therapy (ART, n = 50) or long‐term non‐progressors (LTNPs, n = 24) compared to healthy controls (HCs, n = 38). Methods RNA sequencing (RNAseq), flow cytometry‐based immunophenotyping and functional assays were performed to study Tregs in different HIV cohorts. Results Our RNAseq analysis revealed that Tregs exhibit different transcriptional profiles in HIV‐infected individuals. While Tregs from patients on ART upregulate pathways associated with a more suppressive (activated) phenotype, Tregs in LTNPs exhibit upregulation of pathways associated with impaired suppressive properties. These observations may explain a higher propensity for autoimmune diseases in LTNPs. Also, we found substantial upregulation of HLA‐F mRNA and HLA‐F protein in Tregs from HIV‐infected subjects compared to healthy individuals. These observations highlight a potential role for this non‐classical HLA in Tregs in the context of HIV infection, which should be investigated further in other chronic viral infections and cancer. Conclusion Our study has provided a novel insight into Tregs at the transcriptional and functional levels in different HIV‐infected groups.

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O-Linked N -Acetylglucosaminylation of Sp1 Inhibits the Human Immunodeficiency Virus Type 1 Promoter

Cited by 38 publications

References 83 publications

Expression of a Protein Phosphatase 1 Inhibitor, cdNIPP1, Increases CDK9 Threonine 186 Phosphorylation and Inhibits HIV-1 Transcription

Expression of a Protein Phosphatase 1 Inhibitor, cdNIPP1, Increases CDK9 Threonine 186 Phosphorylation and Inhibits HIV-1 Transcription

Puerarin suppresses production of nitric oxide and inducible nitric oxide synthase in lipopolysaccharide-induced N9 microglial cells through regulating MAPK phosphorylation, O-GlcNAcylation and NF-κB translocation

Differential transcriptional and functional properties of regulatory T cells in HIV‐infected individuals on antiretroviral therapy and long‐term non‐progressors

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