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Aging May 2022
Topics: Aging; HIV Infections; Humans; tat Gene Products, Human Immunodeficiency Virus
PubMed: 35622387
DOI: 10.18632/aging.204105 -
FEMS Microbiology Letters Jun 2018The Tat machinery catalyzes the transport of folded proteins across the cytoplasmic membrane in bacteria and the thylakoid membrane in plants. Transport occurs only in... (Review)
Review
The Tat machinery catalyzes the transport of folded proteins across the cytoplasmic membrane in bacteria and the thylakoid membrane in plants. Transport occurs only in the presence of an electric field (Δψ) and/or a pH (ΔpH) gradient, and thus, Tat transport is considered to be dependent on the proton motive force (pmf). This presents a fundamental and major challenge, namely, that the Tat system catalyzes the movement of large folded protein cargos across a membrane without collapse of ion gradients. Current models argue that the active translocon assembles de novo for each cargo transported, thus providing an effective gating mechanism to minimize ion leakage. A limited structural understanding of the intermediates occurring during transport and the role of the pmf in stabilizing and/or driving this process have hindered the development of more detailed models. A fundamental question that remains unanswered is whether the pmf is actually 'consumed', providing an energetic driving force for transport, or alternatively, whether its presence is instead necessary to provide the appropriate environment for the translocon components to become active. Including addressing this issue in greater detail, we explore a series of additional questions that challenge current models, and, hopefully, motivate future work.
Topics: Bacteria; Gene Products, tat; Hydrogen-Ion Concentration; Membrane Potentials; Membrane Transport Proteins; Protein Folding; Protein Sorting Signals; Protein Transport; Proton-Motive Force
PubMed: 29897510
DOI: 10.1093/femsle/fny123 -
Current Opinion in Structural Biology Aug 2014The Tat protein transport system is found in the cytoplasmic membrane of prokaryotes and the thylakoid membrane of plant chloroplasts. Unusually, the Tat system... (Review)
Review
The Tat protein transport system is found in the cytoplasmic membrane of prokaryotes and the thylakoid membrane of plant chloroplasts. Unusually, the Tat system translocates proteins only after they have folded. Proteins are targeted to the Tat system by specific N-terminal signal peptides. High resolution structures have recently been determined for the TatA and TatC proteins that form the Tat translocation site. These structures provide a molecular framework for understanding the mechanism of Tat transport. The interactions between TatC and the signal peptide of the substrate protein can be provisionally modelled. However, the way that TatA and TatC combine in the active translocation site remains to be definitively established.
Topics: Gene Products, tat; Protein Sorting Signals; Protein Transport
PubMed: 24709396
DOI: 10.1016/j.sbi.2014.03.003 -
Virology Journal Dec 2013Nearly 50% of HIV-infected individuals suffer from some form of HIV-associated neurocognitive disorders (HAND). HIV-1 Tat (a key HIV transactivator of transcription)... (Review)
Review
Nearly 50% of HIV-infected individuals suffer from some form of HIV-associated neurocognitive disorders (HAND). HIV-1 Tat (a key HIV transactivator of transcription) protein is one of the first HIV proteins to be expressed after infection occurs and is absolutely required for the initiation of the HIV genome transcription. In addition to its canonical functions, various studies have shown the deleterious role of HIV-1 Tat in the development and progression of HAND. Within the CNS, only specific cell types can support productive viral replication (astrocytes and microglia), however Tat protein can be released form infected cells to affects HIV non-permissive cells such as neurons. Therefore, in this review, we will summarize the functions of HIV-1 Tat proteins in neural cells and its ability to promote HAND.
Topics: Central Nervous System; HIV-1; Host-Pathogen Interactions; Humans; Virulence Factors; tat Gene Products, Human Immunodeficiency Virus
PubMed: 24359561
DOI: 10.1186/1743-422X-10-358 -
Nature Structural & Molecular Biology Apr 2017Deposition of amyloid-β plaques is increased in the brains of HIV-infected individuals, and the HIV transactivator of transcription (Tat) protein affects...
Deposition of amyloid-β plaques is increased in the brains of HIV-infected individuals, and the HIV transactivator of transcription (Tat) protein affects amyloidogenesis through several indirect mechanisms. Here, we investigated direct interactions between Tat and amyloid-β peptide. Our in vitro studies showed that in the presence of Tat, uniform amyloid fibrils become double twisted fibrils and further form populations of thick unstructured filaments and aggregates. Specifically, Tat binding to the exterior surfaces of the Aβ fibrils increases β-sheet formation and lateral aggregation into thick multifibrillar structures, thus producing fibers with increased rigidity and mechanical resistance. Furthermore, Tat and Aβ aggregates in complex synergistically induced neurotoxicity both in vitro and in animal models. Increased rigidity and mechanical resistance of the amyloid-β-Tat complexes coupled with stronger adhesion due to the presence of Tat in the fibrils may account for increased damage, potentially through pore formation in membranes.
Topics: Amyloid; Amyloid beta-Peptides; Animals; Cells, Cultured; Circular Dichroism; Fluorescent Antibody Technique; Humans; Mice, Transgenic; Microscopy, Atomic Force; Models, Biological; Neurons; Neurotoxins; Protein Aggregates; Protein Binding; Protein Structure, Secondary; Rats, Sprague-Dawley; tat Gene Products, Human Immunodeficiency Virus
PubMed: 28218748
DOI: 10.1038/nsmb.3379 -
International Journal of Molecular... Jan 2024Each time the virus starts a new round of expression/replication, even under effective antiretroviral therapy (ART), the transactivator of viral transcription Tat is one... (Review)
Review
Each time the virus starts a new round of expression/replication, even under effective antiretroviral therapy (ART), the transactivator of viral transcription Tat is one of the first HIV-1 protein to be produced, as it is strictly required for HIV replication and spreading. At this stage, most of the Tat protein exits infected cells, accumulates in the extracellular matrix and exerts profound effects on both the virus and neighbor cells, mostly of the innate and adaptive immune systems. Through these effects, extracellular Tat contributes to the acquisition of infection, spreading and progression to AIDS in untreated patients, or to non-AIDS co-morbidities in ART-treated individuals, who experience inflammation and immune activation despite virus suppression. Here, we review the role of extracellular Tat in both the virus life cycle and on cells of the innate and adaptive immune system, and we provide epidemiological and experimental evidence of the importance of targeting Tat to block residual HIV expression and replication. Finally, we briefly review vaccine studies showing that a therapeutic Tat vaccine intensifies ART, while its inclusion in a preventative vaccine may blunt escape from neutralizing antibodies and block early events in HIV acquisition.
Topics: Humans; HIV Infections; HIV-1; tat Gene Products, Human Immunodeficiency Virus; Antibodies, Neutralizing; Vaccines
PubMed: 38338977
DOI: 10.3390/ijms25031704 -
Retrovirology Aug 2006The SWI/SNF chromatin remodeling complex is an essential regulator of transcription of cellular genes. HIV-1 infection induces exit of a core component of SWI/SNF, Ini1,...
The SWI/SNF chromatin remodeling complex is an essential regulator of transcription of cellular genes. HIV-1 infection induces exit of a core component of SWI/SNF, Ini1, into the cytoplasm and its association with the viral pre-integration complex. Several recent papers published in EMBO Journal, Journal of Biological Chemistry, and Retrovirology provide new information regarding possible functions of Ini1 and SWI/SNF in HIV life cycle. It appears that Ini1 has an inhibitory effect on pre-integration steps of HIV replication, but also contributes to stimulation of Tat-mediated transcription. This stimulation involves displacement of the nucleosome positioned at the HIV promoter.
Topics: Chromatin Assembly and Disassembly; Chromosomal Proteins, Non-Histone; DNA-Binding Proteins; Gene Products, tat; HIV Long Terminal Repeat; HIV-1; Humans; SMARCB1 Protein; Transcription Factors; Transcription, Genetic; Virus Replication; tat Gene Products, Human Immunodeficiency Virus
PubMed: 16899112
DOI: 10.1186/1742-4690-3-49 -
Cell Reports Mar 2023A successful HIV-1 cure strategy may require enhancing HIV-1 latency to silence HIV-1 transcription. Modulators of gene expression show promise as latency-promoting...
A successful HIV-1 cure strategy may require enhancing HIV-1 latency to silence HIV-1 transcription. Modulators of gene expression show promise as latency-promoting agents in vitro and in vivo. Here, we identify Su(var)3-9, enhancer-of-zeste, and trithorax (SET) and myeloid, Nervy, and DEAF-1 (MYND) domain-containing protein 5 (SMYD5) as a host factor required for HIV-1 transcription. SMYD5 is expressed in CD4 T cells and activates the HIV-1 promoter with or without the viral Tat protein, while knockdown of SMYD5 decreases HIV-1 transcription in cell lines and primary T cells. SMYD5 associates in vivo with the HIV-1 promoter and binds the HIV trans-activation response (TAR) element RNA and Tat. Tat is methylated by SMYD5 in vitro, and in cells expressing Tat, SMYD5 protein levels are increased. The latter requires expression of the Tat cofactor and ubiquitin-specific peptidase 11 (USP11). We propose that SMYD5 is a host activator of HIV-1 transcription stabilized by Tat and USP11 and, together with USP11, a possible target for latency-promoting therapy.
Topics: HIV-1; Lysine; Methyltransferases; RNA; RNA, Viral; tat Gene Products, Human Immunodeficiency Virus; Transcription, Genetic
PubMed: 36897778
DOI: 10.1016/j.celrep.2023.112234 -
Journal of Neurovirology Dec 2016HIV-1 Tat is an indispensible transactivator for HIV gene transcription and replication. It has been shown to exit cells as a free protein and enter neighboring cells or...
HIV-1 Tat is an indispensible transactivator for HIV gene transcription and replication. It has been shown to exit cells as a free protein and enter neighboring cells or interact with surface receptors of neighboring cells to regulate gene expression and cell function. In this study, we report, for the first time, exosome-associated Tat release and uptake. Using a HIV-1 LTR-driven luciferase reporter-based cell assay and Western blotting or in combination with exosome inhibitor, OptiPrep gradient fractionation, and exosome depletion, we demonstrated significant presence of HIV-1 Tat in exosomes derived from Tat-expressing primary astrocytes, Tat-transfected U373.MG and 293T, and HIV-infected MT4. We further showed that exosome-associated Tat from Tat-expressing astrocytes was capable of causing neurite shortening and neuron death, further supporting that this new form of extracellular Tat is biologically active. Lastly, we constructed a Tat mutant deleted of its basic domain and determined the role of the basic domain in Tat trafficking into exosomes. Basic domain-deleted Tat exhibited no apparent effects on Tat trafficking into exosomes, while maintained its dominant-negative function in Tat-mediated LTR transactivation. Taken together, these results show a significant fraction of Tat is secreted and present in the form of exosomes and may contribute to the stability of extracellular Tat and broaden the spectrum of its target cells.
Topics: Astrocytes; Cell Line, Transformed; Exosomes; Gene Expression; HEK293 Cells; HIV Long Terminal Repeat; HIV-1; Humans; Lymphocytes; Neuroglia; Primary Cell Culture; Protein Domains; Protein Transport; Transcriptional Activation; Transgenes; tat Gene Products, Human Immunodeficiency Virus
PubMed: 27173397
DOI: 10.1007/s13365-016-0451-6 -
CNS Drug Reviews 2005The delivery of proteins across the blood-brain barrier is severely limited by their size and biochemical properties. Numerous peptides have been characterized in recent... (Review)
Review
The delivery of proteins across the blood-brain barrier is severely limited by their size and biochemical properties. Numerous peptides have been characterized in recent years that prevent neuronal death in vitro, but cannot be used therapeutically, since they do not cross cell membrane barriers. It has been shown in the 1990s that the HIV TAT protein is able to cross cell membranes even when coupled with larger peptides. It appears, therefore, that TAT fusion proteins may enter the brain, even when used systemically. Indeed, the systemic delivery of a TAT protein linked with glial-derived neurotrophic factor (GDNF) successfully transduced central nervous system (CNS) neurons in mice. When administered after optic nerve transection and focal cerebral ischemia, TAT-GDNF protected retinal ganglion cells and brain neurons from cell death, elevated tissue Bcl-XL levels and attenuated the activity of the executioner caspase-3. These findings demonstrate the in vivo efficacy of fusion proteins in clinically relevant disease models, raising hopes that neuroprotection may become eventually feasible in human patients.
Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Cell Death; Disease Models, Animal; Gene Products, tat; Genetic Therapy; Glial Cell Line-Derived Neurotrophic Factor; Humans; In Situ Nick-End Labeling; Neurodegenerative Diseases; Recombinant Fusion Proteins
PubMed: 16614736
DOI: 10.1111/j.1527-3458.2005.tb00054.x