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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 -
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 -
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 -
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 -
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 -
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 -
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 -
BMC Infectious Diseases Mar 2023HIV-1 remains a global health concern and to date, nearly 38 million people are living with HIV. The complexity of HIV-1 pathogenesis and its subsequent prevalence is... (Review)
Review
HIV-1 remains a global health concern and to date, nearly 38 million people are living with HIV. The complexity of HIV-1 pathogenesis and its subsequent prevalence is influenced by several factors including the HIV-1 subtype. HIV-1 subtype variation extends to sequence variation in the amino acids of the HIV-1 viral proteins. Of particular interest is the transactivation of transcription (Tat) protein due to its key function in viral transcription. The Tat protein predominantly functions by binding to the transactivation response (TAR) RNA element to activate HIV-1 transcriptional elongation. Subtype-specific Tat protein sequence variation influences Tat-TAR binding affinity. Despite several studies investigating Tat-TAR binding, it is not clear which regions of the Tat protein and/or individual Tat amino acid residues may contribute to TAR binding affinity. We, therefore, conducted a scoping review on studies investigating Tat-TAR binding. We aimed to synthesize the published data to determine (1) the regions of the Tat protein that may be involved in TAR binding, (2) key Tat amino acids involved in TAR binding and (3) if Tat subtype-specific variation influences TAR binding. A total of thirteen studies met our inclusion criteria and the key findings were that (1) both N-terminal and C-terminal amino acids outside the basic domain (47-59) may be important in increasing Tat-TAR binding affinity, (2) substitution of the amino acids Lysine and Arginine (47-59) resulted in a reduction in binding affinity to TAR, and (3) none of the included studies have investigated Tat subtype-specific substitutions and therefore no commentary could be made regarding which subtype may have a higher Tat-TAR binding affinity. Future studies investigating Tat-TAR binding should therefore use full-length Tat proteins and compare subtype-specific variations. Studies of such a nature may help explain why we see differential pathogenesis and prevalence when comparing HIV-1 subtypes.
Topics: Humans; HIV-1; tat Gene Products, Human Immunodeficiency Virus; HIV Long Terminal Repeat; Amino Acids; RNA, Viral
PubMed: 36932337
DOI: 10.1186/s12879-023-08123-0 -
Acta Crystallographica. Section F,... May 2012The superoxide dismutase (SOD) family of proteins are necessary to protect oxygen-utilizing cells from the toxicity of reactive oxygen species. The delivery of SOD into...
The superoxide dismutase (SOD) family of proteins are necessary to protect oxygen-utilizing cells from the toxicity of reactive oxygen species. The delivery of SOD into tissues is severely limited by its size and biochemical properties. A cell-membrane-permeable SOD, SOD-TAT, has been demonstrated to have the ability to be directly transduced into mammalian cells. In this study, the SOD-TAT fusion protein was expressed, purified and crystallized. Crystals of the SOD-TAT fusion protein diffracted to 3.20 Å resolution and belonged to space group C121.
Topics: Crystallization; Crystallography, X-Ray; Gene Products, tat; Recombinant Proteins; Superoxide Dismutase
PubMed: 22691784
DOI: 10.1107/S1744309112012031