The presence of the casein kinase II phosphorylation sites of Vpu enhances the CD4+ T cell loss caused by the simian–human immunodeficiency virus SHIVKU-lbMC33 in pig-tailed macaques

Singh, Dinesh Kumar; Griffin, Darcy M.; Pacyniak, Erik; Jackson, Mollie; Werle, M. J.; Wisdom, Bo; Sun, Francis; Hout, David R.; Pinson, David M.; Gunderson, Robert S.; Powers, Michael F.; Wong, Scott W.; Stephens, Edward B.

doi:10.1016/s0042-6822(03)00339-8

Cited by 31 publications

(40 citation statements)

References 39 publications

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“…Phosphorylation by CK2 results in increased enzymatic activity of both the HIV-1 reverse transcriptase and protease, and inhibition of CK2 reverses activation [135,136]. In a macaque model, mutation of CK2 phosphorylation sites in the SHIV (simian/human immunodeficiency virus) to glycine resulted in decreased T cell loss, indicating that CK2 phosphorylation may contribute to the pathogenicity of HIV-1 [137]. Interestingly, several drugs investigated as HIV inhibitors have been demonstrated to selectively inhibit CK2 [138].…”

Section: Ck2 In Viral Infectionmentioning

confidence: 99%

Protein Kinase CK2 in Health and Disease

St‐Denis

Litchfield

2009

Cell. Mol. Life Sci.

242

102

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Protein kinase CK2 is a serine/threonine kinase with a multitude of protein substrates. The enzyme is ubiquitously expressed in mammalian cells, where it functions in a variety of cellular processes, including cell cycle progression, apoptosis, transcription, and viral infection. While the importance of CK2 in the mammalian life cycle is undisputed, the regulatory mechanisms coordinating its numerous functions remain elusive. In this review, we focus on the various roles of CK2 in the mammalian cell, with particular attention on its functions through the stages of the cell cycle and during the decision to undergo cell death. We highlight how these roles are controlled in part through direct transcriptional regulation by CK2, and how the constitutive activity of CK2 can be hijacked in the case of viral infection. Finally, we discuss possible ways in which these functions are integrated to allow the cell to respond appropriately in the presence of multiple signals.

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Section: Ck2 In Viral Infectionmentioning

confidence: 99%

Protein Kinase CK2 in Health and Disease

St‐Denis

Litchfield

2009

Cell. Mol. Life Sci.

242

102

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“…SIV cpz CAM13, SIV cpz ANT, and SIV cpz TAN1 only contain a single casein kinase II site. All four vpu isolates were fused in frame to the gene for enhanced green fluorescence protein (EGFP) and expressed under the control of a CMV promoter, similar to the HIV-1 subtype B vpu genes our laboratory has previously analyzed [34, 35, 74]. All four SIV cpz Vpu fusion proteins were membrane-associated, partially co-localized with DsRed-ER and ECFP-Golgi marker proteins, and completely co-localized with an ECFP-Membrane marker.…”

Section: The Cd4 Down-modulation Function Is Conserved In Vpu Proteinmentioning

confidence: 99%

The Vpu Protein: New Concepts in Virus Release and CD4 Down-Modulation

Ruiz

Stephens

2010

CHR

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Human immunodeficiency virus type 1 (HIV-1) and several simian immunodeficiency viruses (SIV) encode for a transmembrane protein known as Vpu. While the smallest of the HIV-1 proteins, it has two important functions within virus-infected cells. The first of these functions is the down-regulation of the CD4 receptor to prevent its interaction with the HIV-1 envelope glycoprotein. Vpu interacts with the CD4 receptor in the rough endoplasmic reticulum (RER), resulting in its re-translocation across the RER and subsequent degradation via the proteasomal pathway. The second major function of the Vpu protein is to facilitate release of virus from infected cells. Previous studies have shown that virus release is cell type specific, suggesting that certain cells may express a restriction factor that inhibits virus release in the absence of Vpu. Recently, bone marrow stromal antigen 2 (BST-2/HM124/CD317/tetherin) has been identified as this factor. This review will focus on new findings within the last four years on the role of Vpu in CD4 down-regulation and the restriction of virus release from cells. We will relate these findings to virus pathogenesis and propose questions regarding BST-2 as a restriction factor.

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“…[1][2][3] Studies in a macaque model have shown that Vpu from subtype B plays a crucial role in massive loss of circulating CD4 ϩ T lymphocytes, [4][5][6] which can be modulated by replacing it with Vpu from subtype C. 7 The exact mechanism(s) underlying how Vpu makes HIV-1 more pathogenic is only partially understood. 8,9 Vpu is involved in ubiquitination and degradation of antiretroviral restriction factor BM stromal cell Ag 2 (BST-2; also known as tetherin) and surface receptor CD4 through their recruitment to SCF ␤-TrcP (Skp1/Cul1/F-box) ubiquitin ligase (SCF) complex.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of β-TrcP–dependent ubiquitination of p53 by HIV-1 Vpu promotes p53–mediated apoptosis in human T cells

Verma

Ali

Arora

et al. 2011

Blood

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IntroductionHIV type 1 (HIV-1) Vpu (viral protein U) is an accessory gene exclusive to HIV-1 but not present in HIV-2 and in most SIVs. [1][2][3] Studies in a macaque model have shown that Vpu from subtype B plays a crucial role in massive loss of circulating CD4 ϩ T lymphocytes, 4-6 which can be modulated by replacing it with Vpu from subtype C. 7 The exact mechanism(s) underlying how Vpu makes HIV-1 more pathogenic is only partially understood. 8,9 Vpu is involved in ubiquitination and degradation of antiretroviral restriction factor BM stromal cell Ag 2 (BST-2; also known as tetherin) and surface receptor CD4 through their recruitment to SCF ␤-TrcP (Skp1/Cul1/F-box) ubiquitin ligase (SCF) complex. [10][11][12][13] The key to biologic function of Vpu is the presence of a highly conserved 6-amino acid (DS 52 GNES 56 ) sequence that constitutes the ␤-TrcP (␤-transducin repeat-containing proteins) binding motif. 14 This motif is constitutively phosphorylated and mediates interaction of Vpu with ␤-TrcP, the substrate recognition subunit of SCF ␤-TrcP complex. Hence, Vpu acts as an adaptor linking its target proteins (CD4 and BST-2) to a host E3 ubiquitin ligase SCF ␤-TrcP complex, which are otherwise not the natural substrates of this complex. However, unlike natural substrates of ␤-TrcP, which are targeted for degradation, Vpu itself is resistant to degradation and can form stable complexes with ␤-TrcP. 15 Thus, expression of constitutively phosphorylated Vpu in infected cells leads to competitive inhibition of ubiquitination and subsequent proteosomal degradation of many natural substrates of SCF ␤-TrcP complex (␤-catenin, activating transcription factor 4, and I␤-␣) and results in changes in the profile of cellular proteins that may contribute to cytopathic effects during HIV-1 infection. 9,15,16 The inability to degrade I␤-␣ and to activate NF-␤ on stimulation with TNF-␣ explains the TNF-␣-sensitive phenotype of Vpu-expressing cells. 9 Interestingly, more recent data suggest that Vpu is also degraded by both ␤-TrcPdependent 17 and -independent pathways, 18 which in turn may have a role in modulating biologic activities of Vpu.The SCF ␤-TrcP ubiquitin ligase complex controls the functions of a wide spectrum of cellular proteins 16,[19][20][21][22] ; many of them are involved in pathways crucial to HIV-1 pathology. Tumor suppressor protein p53 is reported to be a major player involved in HIV-1-induced apoptosis. [23][24][25] p53 protein has been shown to be an important substrate of ␤-TrcP-dependent ubiquitination. Small interfering RNA (siRNA)-mediated depletion of components of SCF ␤-TrcP complex or the expression of a dominant-negative form of ␤-TrcP was shown to enhance the stability of p53 protein and also to activate p53 downstream signaling events. 22 Like most of the natural ␤-TrcP substrates (I␤-␣, ␤-catenin, p65, and steroid receptor coactivator 3), the I␤ kinase 2 (IKK2/IKK␤) also phosphorylates p53 at serine 362/366 (Ser362/366) position directing it for ␤-TrcP-mediated ubiquitination in an Mdm-2 ind...

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The presence of the casein kinase II phosphorylation sites of Vpu enhances the CD4+ T cell loss caused by the simian–human immunodeficiency virus SHIVKU-lbMC33 in pig-tailed macaques

Cited by 31 publications

References 39 publications

Protein Kinase CK2 in Health and Disease

Protein Kinase CK2 in Health and Disease

The Vpu Protein: New Concepts in Virus Release and CD4 Down-Modulation

Inhibition of β-TrcP–dependent ubiquitination of p53 by HIV-1 Vpu promotes p53–mediated apoptosis in human T cells

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