The Presence of HIV-1 Tat Protein Second Exon Delays Fas Protein-mediated Apoptosis in CD4+ T Lymphocytes

López-Huertas, María Rosa; Mateos, Elena; Cojo, María Sánchez del; Gómez-Esquer, Francisco; Dı́az-Gil, Gema; Rodríguez-Mora, Sara; López, Juan Antonio; Calvo, Enrique; López-Campos, Guillermo; Alcamı́, José; Coiras, Mayte

doi:10.1074/jbc.m112.408294

Cited by 47 publications

(55 citation statements)

References 118 publications

(113 reference statements)

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“…For example, in vitro , Tat induces cellular FLICE inhibitory protein (cFLIP) expression in T cells 14 including primary T cells and thereby confers resistance to apoptosis. 15 Vpr increases Bcl2 and decreases Bax in the Jurkat T cell line, 16 and there is increased X-linked inhibitor of apoptosis (XIAP) expression in latently infected cell line models. 17 Both Tat-treated monocytes 18 and primary CD4 T cells from HIV-infected patients 19 develop tumor necrosis factor (TNF)-related apoptosis inhibitory protein (TRAIL) resistance, potentially through the production of a novel TRAIL splice variant (TRAILshort), which preferentially binds TRAIL receptor (R)2 and prevents pro-apoptotic TRAIL from signaling.…”

Section: Relationship Between Viral Infection Apoptosis and Viral Pementioning

confidence: 99%

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Altering cell death pathways as an approach to cure HIV infection

et al. 2013

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Recent cases of successful control of human immunodeficiency virus (HIV) by bone marrow transplant in combination with suppressive antiretroviral therapy (ART) and very early initiation of ART have provided proof of concept that HIV infection might now be cured. Current efforts focusing on gene therapy, boosting HIV-specific immunity, reducing inflammation and activation of latency have all been the subject of recent excellent reviews. We now propose an additional avenue of research towards a cure for HIV: targeting HIV apoptosis regulatory pathways. The central enigma of HIV disease is that HIV infection kills most of the CD4 T cells that it infects, but those cells that are spared subsequently become a latent reservoir for HIV against which current medications are ineffective. We propose that if strategies could be devised which would favor the death of all cells which HIV infects, or if all latently infected cells that release HIV would succumb to viral-induced cytotoxicity, then these approaches combined with effective ART to prevent spreading infection, would together result in a cure for HIV. This premise is supported by observations in other viral systems where the relationship between productive infection, apoptosis resistance, and the development of latency or persistence has been established. Therefore we propose that research focused at understanding the mechanisms by which HIV induces apoptosis of infected cells, and ways that some cells escape the pro-apoptotic effects of productive HIV infection are critical to devising novel and rational approaches to cure HIV infection.

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Section: Relationship Between Viral Infection Apoptosis and Viral Pementioning

confidence: 99%

“…20 Another possible mechanism is Tat-mediated upregulation of a variety of nuclear factor kappa-B (NF κ B)-dependent apoptosis inhibitors, including Bcl2, cFLIP, XIAP and CIAP. 21 …”

Section: Relationship Between Viral Infection Apoptosis and Viral Pementioning

confidence: 99%

Altering cell death pathways as an approach to cure HIV infection

et al. 2013

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“…This modulatory activity of Tat has also been implicated in HIV‐uninfected cells, where extracellular Tat can be internalized and directly stimulate cells through a bystander effect . In this scenario, Tat‐mediated signalling triggers an inherent cellular stress arrange, leading to inhibition of lymphocyte proliferation, up‐regulation of genes linked to apoptosis, and overexpression of several cytokines with consequential imbalance of cellular immune status …”

Section: Introductionmentioning

confidence: 99%

HIV‐1 Tat‐induced bystander apoptosis in Jurkat cells involves unfolded protein responses

Campestrini

Silveira

Pinto

2018

Cell Biochemistry & Function

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The HIV transactivator protein (Tat) is a multifunctional protein that plays a critical role in viral replication and contributes to several pathological symptoms of HIV‐1 infection, which has the loss of CD4+ T lymphocytes as one of its hallmark features. It has been shown that endoplasmic reticulum (ER) stress, including viral infections, is implicated in cellular dysfunction and cell death through activation of the unfolded protein response (UPR). Here, we demonstrate that the bystander stimulus of Tat on Jurkat cells resulted in time‐dependent overexpression of major UPR markers including ER chaperone BiP, ER stress sensors ATF6, PERK, and IRE1, as well as an increase in levels of downstream mediators eIF2α, ATF4, XBP‐1, and proapoptotic factors CHOP, GADD34, and BIM. This upregulation of UPR mediators was accompanied by decreased cell viability and increased apoptosis as evidenced by blue trypan dye exclusion and flow cytometry assays, respectively. Furthermore, we found that the Tat‐associated apoptosis of Jurkat cells led to the loss of mitochondrial membrane potential and caspase‐12 and ‐3 activation. Taken together, these results suggest that the exposure of HIV‐1 Tat leads to ER stress/UPR triggering which in turn contributes to apoptotic death in Jurkat cells. Significance of the study In the present work, we provide a substantial insight into the link between ER impairment and apoptotic death following a bystander HIV Tat stimulus, revealing an underlying ER‐mediated apoptotic mechanism which could explain the continuous depletion of uninfected CD4+ T lymphocytes observed in HIV‐related disease. Our findings reinforce the relevance of ER stress molecular responses in the course of HIV infection and may afford valuable information for the development of new therapeutic strategies to avoid CD4+ T lymphocyte loss and other disorders induced by circulant Tat.

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“…However, HIV infection up-regulates the expression of HEBP2 via Tat, which might contribute to the formation of HEBP2/ALG-2 complexes within infected cells and drive HEBP2 to influence ALG-2 under physiological conditions (29).…”

Section: Figure 10 Knockdown Of Endogenous Alg-2 Expression In Hela mentioning

confidence: 99%

“…Unlike p22 HBP , the ability of HEBP2 to bind heme is controversial, and its roles in heme-related activities, such as the generation of reactive oxygen species, are poorly defined. The involvement of HEBP2 in HIV-related activities was suggested in a recent report (29) showing that HIV Tat up-regulates HEBP2 expression. However, the mechanism underlying this effect is unknown.…”

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confidence: 99%

Structural and Functional Study of Apoptosis-linked Gene-2·Heme-binding Protein 2 Interactions in HIV-1 Production

Zhang²,

Feng

et al. 2016

Journal of Biological Chemistry

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Edited by Dennis VoelkerIn the HIV-1 replication cycle, the endosomal sorting complex required for transport (ESCRT) machinery promotes viral budding and release in the late stages. In this process, the ESCRT proteins, ALIX and TSG101, are recruited through interactions with HIV-1 Gag p6. ALG-2, also known as PDCD6, interacts with both ALIX and TSG101 and bridges ESCRT-III and ESCRT-I. In this study, we show that ALG-2 affects HIV-1 production negatively at both the exogenous and endogenous levels. Through a yeast two-hybrid screen, we identified HEBP2 as the binding partner of ALG-2, and we solved the crystal structure of the ALG-2⅐HEBP2 complex. The function of ALG-2⅐HEBP2 complex in HIV-1 replication was further explored. ALG-2 inhibits HIV-1 production by affecting Gag expression and distribution, and HEBP2 might aid this process by tethering ALG-2 in the cytoplasm.The endosomal sorting complex required for transport (ESCRT) 3 machinery functions in HIV-1 budding and release in the late stages of viral replication (1-3). In this process, ALIX (ALG-2 interacting protein X) and TSG101 (tumor susceptibility gene 101), components of ESCRT-III and ESCRT-I, are recruited to the budding site of HIV-1 through interactions with HIV-1 Gag p6 (4 -8). This promotes the release of virion particles (9) with the help of AAA-ATPase VPS4B (vacuolar protein sorting 4 homolog B) (10, 11). The penta-EF-hand protein ALG-2 (apoptosis-linked gene-2, also known as PDCD6) participates in the process by interacting with both ALIX (12, 13) and TSG101 (14) in a calcium-dependent manner and bridges ESCRT-III and ESCRT-I through dimerization (15)(16)(17). However, the function of ALG-2 in viral replication, especially that of HIV-1, remains unknown.ALG-2 was first identified in a functional screen for anti-apoptotic proteins involved in T-cell receptor, Fas, and glucocorticoid-induced cell death (18). It was defined as a proapoptotic molecule because expression of its antisense strand led to rescue from cell death (19). However, ALG-2 knock-out mice are viable and exhibit normal T-cell development (20), which suggested that other redundant proteins might exist in mammalian cells. ALG-2 is a penta-EF-hand protein (13, 15), containing five repeats of the EF-hand motif, and coordinates three calcium ions via EF1, EF3, and EF5. However, the coordination of calcium by EF5 is weak and may be physiologically unimportant. ALG-2 exists as a dimer, which might be critical for its function as an adaptor molecule in signal transduction (15). ALG-2 can interact with dozens of proteins through several pockets (pockets 1-3) on its molecular surface. The binding motif for ALG-2, designated as the ALG-2-binding site (ABS), is a short sequence rich in Pro, Gly, and Tyr. Two typical ABS sequences have been described. ABS-1, which is represented as PPYPXXPGYP (X represents any residue) and occupies pocket 1 on the ALG-2 surface, is found in ALIX and PLSCR3 (6), whereas ABS-2, containing a PXPGF sequence that binds pocket 3, is found in SEC31 and PLSCR3 (1...

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The Presence of HIV-1 Tat Protein Second Exon Delays Fas Protein-mediated Apoptosis in CD4+ T Lymphocytes

Cited by 47 publications

References 118 publications

Altering cell death pathways as an approach to cure HIV infection

Altering cell death pathways as an approach to cure HIV infection

HIV‐1 Tat‐induced bystander apoptosis in Jurkat cells involves unfolded protein responses

Structural and Functional Study of Apoptosis-linked Gene-2·Heme-binding Protein 2 Interactions in HIV-1 Production

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