HIV-1 Nef Promotes Survival of TF-1 Macrophages by Inducing Bcl-X Expression in an Extracellular Signal-regulated Kinase-dependent Manner

Choi, Hyun-Jung; Smithgall, Thomas E.

doi:10.1074/jbc.m410068200

Cited by 36 publications

(32 citation statements)

References 50 publications

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“…RPA was performed by using the BD Riboquant package kit (BD Biosciences) with a multiprobe template set of anti-and proapoptotic genes of the Bcl2 family along with internal controls (glyceraldehyde-3-phosphate dehydrogenase/␤-actin) according to the manufacturer's protocol (34). Briefly 32 P-labeled riboprobes of defined length were generated using T7 RNA polymerase and 50 ng of DNA template in the presence of 150 Ci of [␣-…”

Section: Isolation Of Monocytes From Peripheral Blood Mononuclearmentioning

confidence: 99%

Activation of JNK-dependent Pathway Is Required for HIV Viral Protein R-induced Apoptosis in Human Monocytic Cells

Mishra

Kumar

2007

Journal of Biological Chemistry

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Human immunodeficiency virus (HIV) accessory protein viral protein R (Vpr) plays a key role in virus replication and induces cell cycle arrest and apoptosis in various cell types including T cells and neuronal and tumor cells following infection withApoptosis is an active process mediated by programmed signaling pathways that can be initiated by a variety of intracellular and extracellular stimuli. Apoptosis is essential to many biological processes including functional self-organizational processes in the immune and central nervous systems, morphogenetic changes in embryonic development, tissue homeostasis, and normal cell turnover (1). It also plays a critical role in the pathogenesis of a variety of diseases including cancer and infectious diseases (1, 2). Modulation of apoptosis may be closely associated with the outcome of a disease process. For example, resistance to apoptosis is one of the important mechanisms by which cancer cells evade destruction by the immune system (1). Therefore, effective therapies against such diseases should ideally induce efficient cytotoxicity to override apoptotic resistance. Recently the viral protein R (Vpr) 3 of the human immunodeficiency virus (HIV) has been proposed as a novel antiproliferative agent in vivo because of its ability to induce apoptosis in normal and tumor cell lines, including leukemialymphoma, colon, and cervical carcinoma cell lines (3, 4), and its ability to transduce cells effectively without carriers or receptor targeting strategies (5, 6).Vpr, a 14-kDa 96-amino acid protein, is the most conserved and multifunctional regulatory protein. It plays a key role in virus replication by causing nuclear translocation of the HIV-1 preintegration complex and transcriptional regulation of the HIV long terminal repeat (7-10). It has also been shown to induce cell cycle arrest at the G 2 /M phase and apoptosis in a variety of cell types including T cells, neutrophils, and neuronal cells following infection with Vpr-expressing HIV isolates or exposure to the extracellular Vpr protein (7,11). Recently Vpr was detected in the sera and cerebrospinal fluid of HIV-infected subjects at levels similar to those of p24 antigen (5, 12). Moreover circulating Vpr was found to be biologically active in inducing virion production from latently infected cells, inducing apoptosis and causing depletion of bystander cells in lymphoid tissues during HIV infection (5,12).Multiple functions of Vpr have been attributed to its different domains (13). The Vpr protein is characterized by three well defined ␣-helices: 17-33, 40 -48, and 55-83 surrounded by flexible negatively charged N-terminal and basic C-terminal * This work was supported in part by grants from the Canadian Institutes of Health Research (to A. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 (14). Furthermore the amphipathic ␣-helix 55-83...

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Section: Isolation Of Monocytes From Peripheral Blood Mononuclearmentioning

confidence: 99%

Activation of JNK-dependent Pathway Is Required for HIV Viral Protein R-induced Apoptosis in Human Monocytic Cells

Mishra

Kumar

2007

Journal of Biological Chemistry

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“…For example, ERK has been reported to be an important macrophage survival factor in some (35)(36)(37)(38)(39)(40) but not all (30,41,42) studies, and we detected decreased ERK phosphorylation in response to LPS or thapsigargin in BMDMs from both WT and BCAP-deficient mice, as well as a trend for enhanced ERK phosphorylation in unchallenged BMDMs from BCAP-deficient mice (Fig. 4).…”

Section: Bcap Is Required For Maximal Activation Of Akt In Response Tmentioning

confidence: 60%

A Requirement for the p85 PI3K Adapter Protein BCAP in the Protection of Macrophages from Apoptosis Induced by Endoplasmic Reticulum Stress

Song

Chew

Dale

et al. 2011

The Journal of Immunology

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Macrophages are innate immune cells that play key roles in regulation of the immune response and in tissue injury and repair. In response to specific innate immune stimuli, macrophages may exhibit signs of endoplasmic reticulum (ER) stress and progress to apoptosis. Factors that regulate macrophage survival under these conditions are poorly understood. In this study, we identified B cell adapter protein (BCAP), a p85 PI3K-binding adapter protein, in promoting survival in response to the combined challenge of LPS and ER stress. BCAP was unique among nine PI3K adapter proteins in being induced >10-fold in response to LPS. LPS-stimulated macrophages incubated with thapsigargin, a sarcoplasmic/endoplasmic reticulum calcium ATPase inhibitor that induces ER stress, underwent caspase-3 activation and apoptosis. Macrophages from BCAP−/− mice exhibited increased apoptosis in response to these stimuli. BCAP-deficient macrophages demonstrated decreased activation of Akt, but not ERK, and, unlike BCAP-deficient B cells, expressed normal amounts of the NF-κB subunits, c-Rel and RelA. Retroviral transduction of BCAP-deficient macrophages with wild-type BCAP, but not a Y4F BCAP mutant defective in binding the SH2 domain of p85 PI3K, reversed the proapoptotic phenotype observed in BCAP-deficient macrophages. We conclude that BCAP is a nonredundant PI3K adapter protein in macrophages that is required for maximal cell survival in response to ER stress. We suggest that as macrophages engage their pathogenic targets, innate immune receptors trigger increased expression of BCAP, which endows them with the capacity to withstand further challenges from ongoing cellular insults, such as ER stress.

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“…Consistent with our findings, He et al (52) recently showed that Nef augments c-Src kinase activity and induces proliferation in immortalized podocytes in a PXXPXR-dependent manner. Activation of c-Src by Nef led to activation of signal transducers and activators of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) signaling downstream, as previously observed in other cell types (16,17). NefSrc interaction may contribute to HIV-1-associated nephropathy, the most common cause of chronic renal failure in HIVseropositive patients (52).…”

Section: Discussionmentioning

confidence: 81%

HIV-1 Nef Selectively Activates Src Family Kinases Hck, Lyn, and c-Src through Direct SH3 Domain Interaction

Trible

Emert-Sedlak

Smithgall

2006

Journal of Biological Chemistry

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132

188

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Nef is an HIV-1 virulence factor that promotes viral pathogenicity by altering host cell signaling pathways. Nef binds several members of the Src kinase family, and these interactions have been implicated in the pathogenesis of HIV/AIDS. However, the direct effect of Nef interaction on Src family kinase (SFK) regulation and activity has not been systematically addressed. We explored this issue using Saccharomyces cerevisiae, a well defined model system for the study of SFK regulation. Previous studies have shown that ectopic expression of c-Src arrests yeast cell growth in a kinase-dependent manner. We expressed Fgr, Fyn, Hck, Lck, Lyn, and Yes as well as c-Src in yeast and found that each kinase was active and induced growth suppression. Co-expression of the negative regulatory kinase Csk suppressed SFK activity and reversed the growth-inhibitory effect. We then co-expressed each SFK with HIV-1 Nef in the presence of Csk. Nef strongly activated Hck, Lyn, and c-Src but did not detectably affect Fgr, Fyn, Lck, or Yes. Mutagenesis of the Nef PXXP motif essential for SH3 domain binding greatly reduced the effect of Nef on Hck, Lyn, and c-Src, suggesting that Nef activates these Src family members through allosteric displacement of intramolecular SH3-linker interactions. These data show that Nef selectively activates Hck, Lyn, and c-Src among SFKs, identifying these kinases as proximal effectors of Nef signaling and potential targets for anti-HIV drug discovery.Nef is an accessory protein encoded by the human (HIV-1 and HIV-2) 2 and simian immunodeficiency viruses and is an essential mediator of viral pathogenicity (1-3). Experimental deletion within the simian immunodeficiency virus nef gene reduces viral load, delays the onset of AIDS-like disease, and offers immune protection against challenge with pathogenic simian immunodeficiency virus in rhesus macaques (4, 5). Strong selective pressure has been demonstrated for a functional nef gene, because some animals infected with non-pathogenic, nef-mutant simian immunodeficiency virus show in vivo repair of the mutation and progression to AIDS-like disease (5-7). In addition, some HIV-positive individuals that fail to develop AIDS exhibit nef mutations or deletions (8 -12), supporting the hypothesis that nef is essential for efficient disease progression.Nef has no known catalytic function and is believed to promote viral pathogenicity by altering signaling pathways in infected cells through its interactions with cellular proteins. Nef affects several distinct classes of host cell proteins, including immune receptors, protein kinases, trafficking proteins, and guanine nucleotide exchange factors (13-15). Through interactions with these and other signaling proteins, Nef can affect multiple cellular processes leading to enhancement of viral replication, immune evasion, and enhanced survival in T-cells and macrophages (1, 16 -18).Protein kinases are a major class of Nef effector proteins, and members of the Src family of non-receptor protein-tyrosine kinases have been str...

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HIV-1 Nef Promotes Survival of TF-1 Macrophages by Inducing Bcl-X Expression in an Extracellular Signal-regulated Kinase-dependent Manner

Cited by 36 publications

References 50 publications

Activation of JNK-dependent Pathway Is Required for HIV Viral Protein R-induced Apoptosis in Human Monocytic Cells

Activation of JNK-dependent Pathway Is Required for HIV Viral Protein R-induced Apoptosis in Human Monocytic Cells

A Requirement for the p85 PI3K Adapter Protein BCAP in the Protection of Macrophages from Apoptosis Induced by Endoplasmic Reticulum Stress

HIV-1 Nef Selectively Activates Src Family Kinases Hck, Lyn, and c-Src through Direct SH3 Domain Interaction

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