The HIV Nef Protein Alters Ca2+ Signaling in Myelomonocytic Cells through SH3-mediated Protein-Protein Interactions

Foti, Michelangelo; Cartier, Laetitia; Piguet, Vincent; Lew, Daniel Pablo; Carpentier, Jean‐Louis; Trono, Didier; Krause, Karl‐Heinz

doi:10.1074/jbc.274.49.34765

Cited by 34 publications

(24 citation statements)

References 66 publications

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“…We first measured the basal internalization rate of CD4 in myeloid (THP-1 and U937), lymphoid (HPB-ALL), and CD4-expressing epithelial (HeLa-CD4) cells using a flow cytometry-based assay. Consistent with published results (18,(49)(50)(51)68), Fig. 1A and Table 1 show that CD4 internalization in HPB-ALL cells followed slow kinetics (1.6%/min) compared with U937, THP-1, and HeLa-CD4 cells, in which the rate of CD4 internalization was two-to fourfold higher (4.5, 6.5, and 3.5%/min, respectively).…”

Section: Resultssupporting

confidence: 79%

Nef-Induced CD4 Endocytosis in Human Immunodeficiency Virus Type 1 Host Cells: Role of p56^lckKinase

Laguette

Brégnard

Bouchet

et al. 2009

J Virol

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Human immunodeficiency virus type 1 (HIV-1) Nef interferes with the endocytic machinery to modulate the cell surface expression of CD4. However, the basal trafficking of CD4 is governed by different rules in the target cells of HIV-1: whereas CD4 is rapidly internalized from the cell surface in myeloid cells, CD4 is stabilized at the plasma membrane through its interaction with the p56 lck kinase in lymphoid cells. In this study, we showed that Nef was able to downregulate CD4 in both lymphoid and myeloid cell lines but that an increase in the internalization rate of CD4 could be observed only in lymphoid cells. Expression of p56 lck in nonlymphoid CD4-expressing cells restores the ability of Nef in order to increase the internalization rate of CD4. Concurrent with this observation, the expression of a p56 lck -binding-deficient mutant of CD4 in lymphoid cells abrogates the Nef-induced acceleration of CD4 internalization. We also show that the expression of Nef causes a decrease in the association of p56 lck with cell surface-expressed CD4. Regardless of the presence of p56 lck , the downregulation of CD4 by Nef was followed by CD4 degradation. Our results imply that Nef uses distinct mechanisms to downregulate the cell surface expression levels of CD4 in either lymphoid or myeloid target cells of HIV-1.

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Section: Resultssupporting

confidence: 79%

Nef-Induced CD4 Endocytosis in Human Immunodeficiency Virus Type 1 Host Cells: Role of p56^lckKinase

Laguette

Brégnard

Bouchet

et al. 2009

J Virol

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“…The neurotoxin protein HIV-Tat activates IP 3 -gated calcium stores in conferring neuronal cell death, which in turn causes AIDS-related dementia complex (42). HIV infection also causes IP 3 R1 to associate with the HIV-1 Nef protein, which promotes the early viral life cycle (43)(44)(45). These findings suggest the possible involvement of IP 3 R-mediated Ca 2ϩ signaling in HIV pathogenesis.…”

Section: Discussionmentioning

confidence: 76%

“…For example, most self-reactive immature B cells having elevated cytoplasmic Ca 2ϩ undergo apoptosis during development (i.e., clonal deletion) to establish immunological tolerance (38 -40), whereas HIV infection causes profound immunological defects in afflicted patients, with high levels of immune activation and apoptosis of CD4 ϩ T cells. The increased frequency of apoptosis of CD4 ϩ T cells in HIV patients and serious perturbations of the cell cycle are associated with increased CyB1 expression and p34 cdc2 activity (41)(42)(43)(44)(45)(46)(47)(48). It is therefore likely that an abnormal relationship between T cell activation/proliferation and the occurrence of apoptosis may play a significant role in lymphocyte depletion in HIV patients.…”

Section: Discussionmentioning

confidence: 99%

Cdc2/Cyclin B1 Interacts with and Modulates Inositol 1,4,5-Trisphosphate Receptor (Type 1) Functions

Malathi

Križanová

et al. 2005

The Journal of Immunology

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The resistance of inositol 1,4,5-trisphosphate receptor (IP3R)-deficient cells to multiple forms of apoptosis demonstrates the importance of IP3-gated calcium (Ca2+) release to cellular apoptosis. However, the specific upstream biochemical events leading to IP3-gated Ca2+ release during apoptosis induction are not known. We have shown previously that the cyclin-dependent kinase 1/cyclin B (cdk1/CyB or cdc2/CyB) complex phosphorylates IP3R1 in vitro and in vivo at Ser421 and Thr799. In this study, we show that: 1) the cdc2/CyB complex directly interacts with IP3R1 through Arg391, Arg441, and Arg871; 2) IP3R1 phosphorylation at Thr799 by the cdc2/CyB complex increases IP3 binding; and 3) cdc2/CyB phosphorylation increases IP3-gated Ca2+ release. Taken together, these results demonstrate that cdc2/CyB phosphorylation positively regulates IP3-gated Ca2+ signaling. In addition, identification of a CyB docking site(s) on IP3R1 demonstrates, for the first time, a direct interaction between a cell cycle component and an intracellular calcium release channel. Blocking this phosphorylation event with a specific peptide inhibitor(s) may constitute a new therapy for the treatment of several human immune disorders.

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“…Additionally, other studies have been completed that utilize these cells to examine the role that distinct viral determinants as well as specific host factors have on cellular tropism, cellular differentiation, and cytopathology [190][191][192][193]. They have also been used in examining the role of CDK9 and characterizing its function based on known interactions with Tat [166] as well as how Nef manipulates intracellular Ca(2+) stores through SH3-mediated interactions in myelomonocytic cells [194].…”

Section: Hl-60mentioning

confidence: 99%

Myelomonocytic Cell Lines in Modeling HIV-1 Infection of the Bone Marrow

Nonnemacher¹,

Quiterio²,

Allen³

et al. 2017

Biology of Myelomonocytic Cells

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Human immunodeficiency virus type 1 (HIV-1), the etiologic agent of acquired immunodeficiency syndrome (AIDS), primarily infects T cells and cells of the monocyte-macrophage lineage. This is due to the presence of the cell surface receptor CD4 and the coreceptors, CXCR4, and CCR5. While the T-cell has classically been the cell type associated with HIV-1 disease progression, cells of the monocyte-macrophage lineage have also been shown to play a major role in this viral pathologic process. Classically, this has involved monocytic cells in the peripheral blood and tissue macrophages, however, over the course of HIV disease, the promyelomonocytic cells of the bone marrow (BM) have also been shown to play a role in pathogenesis retroviral disease in that they play an integral role in the reseeding of the periphery and end-organ tissues. This has involved an initial infection of the bone marrow hematopoietic progenitor cells. Given this observation, over the years there have been a number of cell lines that have been developed and provided valuable insights into research questions surrounding HIV-1 infection of the monocyte-macrophage cell lineage. In this regard, we will examine the biological and immunological properties of these BM-derived cell lines with respect to their utility in exploring the pathogenesis of HIV-1 in humans.

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The HIV Nef Protein Alters Ca2+ Signaling in Myelomonocytic Cells through SH3-mediated Protein-Protein Interactions

Abstract: Human immunodeficiency virus

Cited by 34 publications

References 66 publications

Nef-Induced CD4 Endocytosis in Human Immunodeficiency Virus Type 1 Host Cells: Role of p56^lckKinase

Nef-Induced CD4 Endocytosis in Human Immunodeficiency Virus Type 1 Host Cells: Role of p56^lckKinase

Cdc2/Cyclin B1 Interacts with and Modulates Inositol 1,4,5-Trisphosphate Receptor (Type 1) Functions

Myelomonocytic Cell Lines in Modeling HIV-1 Infection of the Bone Marrow

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The HIV Nef Protein Alters Ca2+ Signaling in Myelomonocytic Cells through SH3-mediated Protein-Protein Interactions

Abstract: Human immunodeficiency virus

Cited by 34 publications

References 66 publications

Nef-Induced CD4 Endocytosis in Human Immunodeficiency Virus Type 1 Host Cells: Role of p56lckKinase

Nef-Induced CD4 Endocytosis in Human Immunodeficiency Virus Type 1 Host Cells: Role of p56lckKinase

Cdc2/Cyclin B1 Interacts with and Modulates Inositol 1,4,5-Trisphosphate Receptor (Type 1) Functions

Myelomonocytic Cell Lines in Modeling HIV-1 Infection of the Bone Marrow

Contact Info

Product

Resources

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Nef-Induced CD4 Endocytosis in Human Immunodeficiency Virus Type 1 Host Cells: Role of p56^lckKinase

Nef-Induced CD4 Endocytosis in Human Immunodeficiency Virus Type 1 Host Cells: Role of p56^lckKinase