Affinage

TAT

Tyrosine aminotransferase · UniProt P17735

Length
454 aa
Mass
50.4 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HIV-1 Tat is a multifunctional viral transactivator whose central function is to drive processive transcriptional elongation from the HIV-1 LTR by binding the nascent TAR RNA stem-loop (PMID:2247474, PMID:1903308) and converting paused polymerase complexes into elongation-competent ones (PMID:1658392, PMID:1752440). Tat is organized into separable functional modules: an arginine-rich basic domain that binds the single-stranded bulge of TAR with nanomolar affinity (PMID:2247474, PMID:1903308), and a distinct activation domain that stimulates processivity even when tethered to RNA through a heterologous binding module (PMID:1658392, PMID:1752440); the activation domain alone also supports transcription when Tat is recruited to promoter DNA, where the RNA-binding domain becomes dispensable (PMID:1752440). Mechanistically, Tat recruits the P-TEFb kinase complex (CDK9/cyclin T1) to TAR, and cyclin T1 itself contributes TAR loop recognition to assemble a ternary Tat-cyclin T1-TAR complex that hyperphosphorylates the RNA Pol II CTD (PMID:10550206), with the cellular elongation cofactor Tat-SF1 and its associated factors SPT5 and the TFIIF subunit RAP30 required for full transactivation (PMID:8849451, PMID:9765201, PMID:10454543). P-TEFb availability for Tat is constrained by HEXIM1, which represses Tat-dependent transcription via cyclin T1 and 7SK snRNA (PMID:15992410). Tat activity is tuned by reversible acetylation: PCAF acetylates Lys28 to enhance P-TEFb binding while p300 acetylates Lys50 to release Tat from TAR during elongation (PMID:10545121), with the acetyl-Lys50 mark read by the PCAF bromodomain to drive synergistic activation (PMID:12032084), and SIRT1 deacetylates Tat to recycle it for further rounds of transcription (PMID:15719057). Beyond elongation, Tat couples to co-transcriptional mRNA capping through direct binding of its C-terminus to the capping enzyme Mce1 (PMID:12408826) and is required in producer cells for efficient reverse transcription of progeny virions (PMID:9135139). Tat acts extracellularly after unconventional secretion that bypasses the ER and occurs at the plasma membrane via PI(4,5)P2 binding (PMID:19995346, PMID:21951552), followed by endocytic uptake and TPC- and calcium-dependent escape from endolysosomes into the cytosol (PMID:31950548); extracellular Tat mimics beta-chemokines by binding CCR2 and CCR3 to trigger monocyte calcium flux and migration (PMID:9789057), and contributes to neurotoxicity through direct engagement of the NMDA receptor NR1 subunit via its Cys30-Cys31 motif (PMID:19020013). Tat protein levels are governed post-translationally by ubiquitin-independent 20S proteasomal degradation of the intrinsically unstructured protein (PMID:27283735) and by USP7-mediated deubiquitination that stabilizes Tat and supports virus production (PMID:28280111).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1990 High

    Established the molecular basis of Tat target recognition by showing Tat binds a specific RNA element rather than acting through DNA alone, defining TAR as the transactivation-response RNA target.

    Evidence In vitro RNA-binding with bacterial Tat and synthetic TAR mutants, Scatchard analysis

    PMID:1903308 PMID:2247474

    Open questions at the time
    • Does not explain why loop mutations abolish activity in vivo despite intact bulge binding in vitro
    • No cellular cofactor identified for TAR engagement
  2. 1991 High

    Resolved how Tat activates transcription by showing it enhances elongation/processivity rather than initiation, and that RNA-binding and activation functions are modular.

    Evidence Domain-swap tethering of Tat activation domains to R17/GAL4 RNA- and DNA-binding modules with LTR reporter assays

    PMID:1658392 PMID:1752440

    Open questions at the time
    • The cellular elongation machinery recruited by the activation domain was not identified
    • Mechanism distinguishing RNA- vs DNA-tethered activation unclear
  3. 1995 High

    Provided the first structural framework for Tat, defining its domain architecture and intrinsic flexibility.

    Evidence 2D NMR spectroscopy and molecular dynamics of recombinant Tat

    PMID:7723010

    Open questions at the time
    • Flexible basic and cysteine-rich regions limit a defined fold
    • No structure of Tat bound to TAR or partners
  4. 1997 High

    Revealed a transcription-independent role by showing Tat is required in producer cells for efficient reverse transcription of progeny virions.

    Evidence tat-deleted virion production, producer- vs target-cell complementation, endogenous reverse transcription assays in PBMCs

    PMID:9135139

    Open questions at the time
    • Molecular mechanism linking Tat to reverse transcription unresolved
    • Whether a virion-incorporated Tat species mediates the effect not defined
  5. 1998 High

    Identified the cellular cofactor network supporting Tat transactivation, placing Tat within the general elongation machinery.

    Evidence Functional complementation cloning of Tat-SF1, reciprocal co-IP with RAP30/hSPT5, immunodepletion/rescue and overexpression assays

    PMID:10454543 PMID:8849451 PMID:9765201

    Open questions at the time
    • Direct vs indirect contacts between Tat and Tat-SF1/SPT5 not fully resolved
    • Stoichiometry within the elongation complex unknown
  6. 1999 High

    Defined the core kinase mechanism by showing Tat recruits P-TEFb (CDK9/cyclin T1) and that cyclin T1 supplies TAR loop recognition, reconciling in vitro binding with in vivo loop requirements.

    Evidence Dominant-negative CDK9, kinase inhibitors, ternary complex assays with cyclin T1 and TAR loop mutants

    PMID:10550206

    Open questions at the time
    • Structural detail of the Tat-cyclin T1-TAR ternary complex not determined here
    • How CTD phosphorylation is coupled to downstream elongation factors unspecified
  7. 1999 High

    Established acetylation as a regulatory switch by mapping two HAT-specific sites with opposing functional consequences for P-TEFb binding and TAR release.

    Evidence In vitro acetylation, Lys28/Lys50 mutagenesis, co-IP and transactivation assays

    PMID:10545121

    Open questions at the time
    • In vivo timing/ordering of the two acetylation events during a transcription cycle not resolved
    • Deacetylation step not yet identified at this stage
  8. 1999 High

    Extended Tat function to the extracellular space by showing it mimics beta-chemokines through CCR2/CCR3 engagement on monocytes.

    Evidence Ca2+ flux, migration, cross-desensitization, and competitive receptor-binding/displacement on CCR2/CCR3-transfected cells

    PMID:9789057

    Open questions at the time
    • Structural basis of Tat-CCR2/CCR3 binding undefined
    • Physiological contribution to pathogenesis in vivo not established
  9. 1999 Medium

    Implicated Tat in neuronal apoptosis via GSK-3beta but clarified the interaction is indirect.

    Evidence GSK-3beta activity assays, co-precipitation, lithium rescue in rat cerebellar granule neurons

    PMID:10428053

    Open questions at the time
    • The intermediary linking Tat to GSK-3beta activation is unknown
    • Co-precipitation without demonstrated direct enzymatic regulation
  10. 2000 Medium

    Identified thrombospondin-1 as a high-affinity extracellular regulator that neutralizes Tat uptake and transactivation before cell-surface engagement.

    Evidence GST-Tat pulldown, Scatchard analysis, internalization and LTR transactivation assays, heparin competition

    PMID:11023976

    Open questions at the time
    • In vivo relevance of TSP-Tat antagonism not shown
    • Single-lab binding characterization
  11. 2002 High

    Connected acetylation to cofactor reading and to a second cotranscriptional step (capping), broadening Tat's elongation coupling.

    Evidence Structural analysis of acetyl-Lys50 Tat bound to PCAF bromodomain with mutagenesis; in vitro cotranscriptional capping assays defining the C-terminal Tat-Mce1 interaction

    PMID:12032084 PMID:12408826

    Open questions at the time
    • Capping data are single-lab in vitro reconstitution
    • How bromodomain reading is temporally integrated with TAR release unresolved
  12. 2005 Medium

    Completed the acetylation cycle by identifying SIRT1 as the deacetylase that recycles Tat for repeated transcription rounds, and added microtubule, mitochondrial, and LIS1 connections.

    Evidence In vitro deacetylation, co-IP, SIRT1-null MEF rescue; tubulin polymerization and mitochondrial cytochrome c assays; biochemical fractionation/co-IP/Y2H for LIS1

    PMID:15691386 PMID:15698475 PMID:15719057

    Open questions at the time
    • Functional consequence of Tat-LIS1 and tubulin effects for infection vs neurotoxicity unclear
    • Tubulin/mitochondrial findings are single-lab in vitro
  13. 2005 Medium

    Defined a negative regulatory arm of P-TEFb availability constraining Tat function.

    Evidence HEXIM1 domain-mutant repression assays and GAL4-CycT1 artificial recruitment with LTR reporters

    PMID:15992410

    Open questions at the time
    • Dynamics of HEXIM1/7SK release to license Tat not resolved here
    • Single-lab functional assays
  14. 2008 Medium

    Established direct receptor- and organelle-level mechanisms of Tat neurotoxicity and effects on ribosome biogenesis.

    Evidence Direct Tat-NR1 binding with Cys31Ser mutagenesis and clade comparison; transgenic Drosophila nucleolar localization with fibrillarin/U3 snoRNA interaction and rRNA processing assays

    PMID:18559082 PMID:19020013

    Open questions at the time
    • NMDA receptor mechanism partly modeling-based
    • rRNA processing effect shown in a model organism system
  15. 2010 Medium

    Defined the unconventional secretion route, showing Tat exits at the plasma membrane via PI(4,5)P2 binding independent of the ER.

    Evidence N-glycosylation reporter chimera, temperature-block, fractionation; PI(4,5)P2 binding, low-pH conformational change and Hsp90/tryptophan studies

    PMID:19995346 PMID:21951552

    Open questions at the time
    • Molecular machinery driving membrane crossing not fully reconstituted
    • Some mechanistic claims compiled review-style
  16. 2016 Medium

    Defined post-translational control of Tat abundance and a lysosome-based neurotoxic mechanism.

    Evidence Cycloheximide chase, MG132 and curcumin-induced 20S degradation assays; GFAP-dependent lysosomal exocytosis with proteomics and ER stress analysis in astrocytes

    PMID:27283735 PMID:27609518

    Open questions at the time
    • Endogenous physiological trigger of 20S degradation unspecified
    • Astrocyte exocytosis pathway is single-lab
  17. 2017 Medium

    Identified USP7 as a deubiquitinase that stabilizes Tat and promotes virus production, complementing ubiquitin-independent turnover.

    Evidence P5091 inhibition, CRISPR USP7 knockout, dose-dependent overexpression, and virus production assays in latently infected T-cells

    PMID:28280111

    Open questions at the time
    • The ubiquitin ligase opposing USP7 not identified
    • Reconciliation with ubiquitin-independent 20S degradation unclear
  18. 2020 Medium

    Resolved how extracellular Tat reaches the cytosol by implicating two-pore channels and endolysosomal calcium in endolysosome escape.

    Evidence TPC pharmacological inhibitors and siRNA, calcium chelation, TRPML1 negative control, and LTR transactivation/escape imaging assays

    PMID:31950548

    Open questions at the time
    • Direct molecular interaction between Tat and TPC machinery not established
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the many Tat activities — elongation, capping, reverse transcription, secretion/uptake, and the multiple neurotoxic and immunomodulatory extracellular functions — are temporally and spatially coordinated within an infection, and how the opposing degradation (20S) and stabilization (USP7) pathways set Tat levels in vivo.
  • No integrated structural model of the Tat-P-TEFb-TAR-cofactor elongation complex
  • The ubiquitin ligase and physiological signals governing Tat turnover are unidentified
  • In vivo contribution of extracellular Tat functions to pathogenesis not quantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 3 GO:0003723 RNA binding 2 GO:0008092 cytoskeletal protein binding 2 GO:0008289 lipid binding 1 GO:0048018 receptor ligand activity 1
Localization
GO:0005576 extracellular region 2 GO:0005634 nucleus 2 GO:0005768 endosome 2 GO:0005886 plasma membrane 2 GO:0005730 nucleolus 1
Pathway
R-HSA-1643685 Disease 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-8953854 Metabolism of RNA 2 R-HSA-162582 Signal Transduction 1
Partners
CCNT1CDK9EP300KAT2BSIRT1SUPT5HTATSF1USP7
Complex memberships
P-TEFb (CDK9/cyclin T1)

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 HIV-1 Tat protein binds selectively to TAR RNA in vitro with specificity mapping to the single-stranded 'bulge' region of the TAR stem-loop; the basic region of Tat is sufficient for TAR RNA binding, forming a one-to-one complex with Kd ~12 nM. Mutations in the bulge reduced affinity 6-10 fold, while loop mutations did not affect Tat binding. In vitro RNA-binding assay with bacterially expressed Tat protein and synthetic TAR RNA; competition assays with TAR mutants; Scatchard analysis Proceedings of the National Academy of Sciences of the United States of America High 1903308 2247474
1991 Tat activates HIV transcription primarily by enhancing transcriptional elongation rather than initiation; a minimal Tat activation domain of ~47 amino acids (HIV-1) or 15 amino acids (EIAV) is sufficient to stimulate processivity of transcription complexes when tethered to nascent RNA. The RNA-binding domain (~10 aa) and activation domain are separable functional modules. Protein fusion experiments tethering Tat activation domains to heterologous RNA-binding domains (bacteriophage R17 coat protein); transcriptional assays on LTR reporters Journal of virology High 1658392 1752440
1991 Tat can function when bound to upstream promoter DNA rather than TAR RNA; the activation domain required for RNA-bound Tat is also required for DNA-bound Tat, but the arginine-rich RNA-binding domain is dispensable for DNA-bound Tat function. Tat activity requires cooperation with promoter-bound cellular transcription factors in both contexts. Protein fusion experiments with GAL4 DNA-binding domain; transcriptional reporter assays; domain mutagenesis Genes & development Medium 1752440
1996 Tat-SF1 is a cellular cofactor required for Tat transactivation; it associates with a cellular kinase and is a substrate of that kinase. Tat-SF1 contains two RNA recognition motifs and an acidic C-terminal half. Co-transfection of Tat-SF1 cDNA specifically modulates Tat activation, and Tat-SF1 functions as a general transcription elongation factor. cDNA isolation by functional complementation; co-transfection transcriptional assays; protein-affinity chromatography; immunodepletion and complementation with recombinant proteins Science (New York, N.Y.) High 8849451 9765201
1999 Tat stimulates transcriptional elongation by recruiting the TAK (Tat-associated kinase) complex, which contains CDK9 and cyclin T1 (P-TEFb), to the transcription machinery via TAR RNA. This results in hyperphosphorylation of the RNA polymerase II CTD. Cyclin T1 participates in TAR RNA recognition and enables Tat to form a ternary complex with TAR RNA only when a functional loop sequence is present, explaining why loop mutations abolish Tat activity in vivo but not Tat-TAR binding in vitro. Dominant-negative CDK9 kinase inhibition assays; kinase inhibitor studies; ternary complex formation assays with cyclin T1 and TAR RNA loop mutants Journal of molecular biology High 10550206
1999 HIV-1 Tat is directly acetylated at two distinct sites by two different HATs: p300 acetylates Lys50 in the TAR RNA binding domain, and PCAF acetylates Lys28 in the activation domain. Acetylation at Lys28 by PCAF enhances Tat binding to CDK9/P-TEFb, while acetylation at Lys50 by p300 promotes dissociation of Tat from TAR RNA during transcription elongation. In vitro acetylation assays; site-directed mutagenesis of Lys28 and Lys50; co-immunoprecipitation; transcriptional activation assays; trichostatin A synergy experiments The EMBO journal High 10545121
1998 Tat-SF1 associates with RAP30 (a subunit of TFIIF) and human SPT5 (hSPT5) in nuclear extracts; immunodepletion of Tat-SF1 abolishes Tat activation which is rescued by recombinant Tat-SF1; overexpression of Tat-SF1 and hSPT5 specifically stimulates Tat transcriptional activity in vivo. RAP74 subunit of TFIIF is not co-immunoprecipitated with Tat-SF1. Co-immunoprecipitation from nuclear extracts; immunodepletion with complementation; overexpression assays; transcriptional activation assays Molecular and cellular biology High 10454543
1999 HIV-1 Tat protein mimics beta-chemokines: it induces rapid transient Ca2+ influx in monocytes/macrophages via pertussis toxin-sensitive receptors, causes monocyte migration, and cross-desensitizes with MCP-1, MCP-3, and eotaxin. Tat displaces beta-chemokines from receptors CCR2 and CCR3 (but not CCR1, CCR4, CCR5), and a Tat peptide (CysL24-51) directly binds cells transfected with CCR2 and CCR3. Ca2+ influx assays; monocyte migration assays; cross-desensitization studies; competitive receptor binding displacement; direct binding to CCR2/CCR3-transfected cells Proceedings of the National Academy of Sciences of the United States of America High 9789057
1999 Tat-induced neuronal apoptosis involves activation of glycogen synthase kinase-3beta (GSK-3beta); Tat co-precipitates with GSK-3beta but direct addition of Tat to purified GSK-3beta has no effect on enzyme activity, indicating Tat's effects on GSK-3beta are indirect. PAF receptor activation also activates GSK-3beta. Lithium (GSK-3beta inhibitor) enhances neuronal survival after Tat exposure. GSK-3beta kinase activity assays; co-precipitation; lithium treatment rescue experiments; PAF receptor activation studies in rat cerebellar granule neurons Journal of neurochemistry Medium 10428053
2002 Transcriptional synergy between Tat and PCAF requires acetylation of Lys50 of Tat and the PCAF bromodomain. Structural analysis defined critical interaction residues: Y47 and R53 in Tat, and V763, Y802, Y809 in PCAF bromodomain. Mutation of these residues inhibits Tat-PCAF interaction in vitro and in vivo and abrogates HIV promoter synergistic activation. In vitro and in vivo binding assays; structural analysis of acetylated Tat peptide bound to PCAF bromodomain; site-directed mutagenesis; HIV promoter transactivation assays The EMBO journal High 12032084
2002 Tat stimulates cotranscriptional capping of HIV mRNA; this stimulation requires the C-terminal segment of Tat that mediates direct binding to the capping enzyme Mce1. Both Mce1 and the cap methyltransferase Hcm1 travel with Pol II during elongation and require CTD phosphorylation for stable binding to template-engaged Pol II. In vitro transcription/capping assays with template-engaged Pol II; domain deletion studies identifying C-terminal Tat-Mce1 binding region; cotranscriptional capping efficiency measurements Molecular cell High 12408826
2005 Tat is deacetylated by SIRT1, a NAD-dependent class III deacetylase, in vitro and in vivo; Tat and SIRT1 co-immunoprecipitate and synergistically activate the HIV promoter. Knockdown of SIRT1 or treatment with SIRT1 inhibitors inhibit Tat-mediated transactivation. Tat transactivation is defective in SIRT1-null MEFs and rescued by SIRT1 re-expression. SIRT1 recycles Tat to its unacetylated form to enable repeated rounds of transcription. In vitro deacetylation assays; co-immunoprecipitation; siRNA knockdown; SIRT1-null MEF rescue experiments; HIV LTR transactivation assays PLoS biology High 15719057
2005 Tat protein directly enhances tubulin polymerization; residues 38-72 of Tat are responsible for this activity. Tat can also directly trigger the mitochondrial apoptosis pathway, as evidenced by release of cytochrome c from isolated mitochondria in vitro. Tubulin polymerization assays with recombinant Tat variants and truncation peptides; cytochrome c release assays from isolated mitochondria; comparison with paclitaxel Retrovirology Medium 15691386
2005 Tat interacts with LIS1, a microtubule-associated protein, in vitro and in vivo. LIS1 was identified during biochemical fractionation of T-cell extracts co-purifying with Tat-associated RNAPII CTD kinase activity. Tat-LIS1 interaction was confirmed by co-IP in HeLa cells and yeast two-hybrid. Tat did not interact directly with CDK7, cyclin H, or MAT1 that co-purify in the same fractions. Biochemical fractionation of T-cell extracts; in vitro binding assay; co-immunoprecipitation from HeLa cells; yeast two-hybrid Retrovirology Medium 15698475
2005 HEXIM1 inhibits Tat transactivation by regulating P-TEFb activity; HEXIM1-mediated repression requires both its 7SK snRNA basic recognition motif and the C-terminal region required for cyclin T1 interaction. HEXIM1 expression specifically represses transcription mediated by direct activation of P-TEFb through artificial recruitment of GAL4-CycT1, and this repression is not due to global inhibition of cellular transcription. Co-expression transcriptional repression assays; HEXIM1 domain mutant analysis; GAL4-CycT1 artificial recruitment assay; HIV LTR reporter assays Retrovirology Medium 15992410
1997 Tat is required for efficient HIV-1 reverse transcription; HIV-1 virions deleted in tat cannot initiate reverse transcription efficiently in PBMCs, despite containing normal levels of genomic RNA, reverse transcriptase, and other viral proteins. Complementation of tat in producer cells (not target cells) rescues the reverse transcription defect, and tat-deleted virions also show defects in endogenous reverse transcription assays. Tat-deleted HIV-1 virion production; infection of PBMCs with complementation in producer vs. target cells; endogenous reverse transcription assays; protein and RNA quantification of virion components The EMBO journal High 9135139
1995 The structure of HIV-1 Tat protein in solution was determined by 2D NMR and molecular dynamics; the protein exhibits a hydrophobic core of 16 amino acids, a glutamine-rich domain of 17 amino acids, a cysteine-rich domain, and a basic sequence region. The basic and cysteine-rich domains are highly flexible. The C-terminal region contains an RGD loop structurally similar to that of decorsin. 2D NMR spectroscopy; molecular dynamics calculations Journal of molecular biology High 7723010
2008 HIV-1 Tat (clade B) binds directly to the NMDA receptor (NR1 subunit) leading to excitotoxicity; the Cys30-Cys31 motif in Tat is critical for NMDA receptor activation. Through molecular modeling and site-directed mutagenesis, Cys31 is predicted to disrupt the disulfide bond between Cys744 and Cys798 on NR1 by interacting with Cys744, leaving a free thiol on Cys798 and causing persistent NMDA receptor activation. The Cys31Ser mutation in clade C Tat significantly attenuates neurotoxicity. Direct Tat-NMDA receptor binding experiments; site-directed mutagenesis (Cys31Ser); molecular modeling; neuronal toxicity assays comparing clade B vs. clade C Tat The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 19020013
2008 HIV-1 Tat localizes in nucleoli of cells and interacts with fibrillarin and U3 snoRNA (both required for pre-rRNA maturation), leading to impaired processing of ribosomal RNA precursors and decreased cytoplasmic ribosomes. Transgenic Drosophila expressing HIV-1 tat; immunolocalization showing co-localization with fibrillarin in nucleoli; ribosomal rRNA precursor processing assays; co-immunoprecipitation/interaction with fibrillarin and U3 snoRNA BMC cell biology Medium 18559082
2010 Tat is secreted by infected CD4+ T-cells through an unconventional pathway that does not involve the endoplasmic reticulum or known intracellular organelles. A Tat chimera with an N-glycosylation site was not glycosylated when expressed in cells but was glycosylated when introduced into purified microsomes, confirming ER-independent secretion. At 16°C, Tat secretion is inhibited and Tat accumulates at the plasma membrane, indicating secretion occurs at the plasma membrane level. N-glycosylation reporter chimera assay; pharmacological inhibitor studies; temperature-block experiments; subcellular fractionation Cell biology international Medium 19995346
2010 Tat secretion by infected cells requires high-affinity binding to phosphatidylinositol(4,5)bisphosphate (PI(4,5)P2) concentrated in the inner leaflet of the plasma membrane, enabling Tat recruitment and membrane crossing. Following secretion, Tat binds various cell-surface receptors, is endocytosed, and low endosomal pH triggers a conformational change enabling membrane insertion. Translocation to the cytosol is assisted by Hsp90. The single tryptophan residue in Tat is important for membrane insertion. PI(4,5)P2 binding studies; conformational change assays at low pH; Hsp90 inhibition studies; tryptophan mutagenesis Traffic (Copenhagen, Denmark) Medium 21951552
2016 HIV-1 Tat protein is degraded by the 20S proteasome in an ubiquitin-independent manner (consistent with its intrinsically unfolded nature); curcumin activates the 20S proteasome and promotes dose- and time-dependent Tat degradation without affecting Tat mRNA levels. Proteasomal inhibitor MG132 blocks curcumin-induced Tat degradation. The properly folded HIV-1 Gag protein is not affected by curcumin. Cycloheximide chase assay; proteasome inhibitor (MG132) experiments; semi-quantitative RT-PCR; dose-response degradation assays in HEK-293T cells Scientific reports Medium 27283735
2017 The deubiquitinase USP7 stabilizes HIV-1 Tat protein through deubiquitination; inhibition of USP7 (by P5091 inhibitor or CRISPR-Cas9 deletion) leads to Tat protein degradation and reduced virus production. USP7 overexpression increases Tat-mediated HIV-1 production in a dose-dependent manner. HIV-1 infection up-regulates endogenous USP7 levels in human T-cells. USP7-specific inhibitor (P5091) and general DUB inhibitor (PR-619) treatment; CRISPR-Cas9 USP7 knockout; dose-dependent overexpression assays; western blot analysis; virus production assays in J1.1 latently infected T-cells The Biochemical journal Medium 28280111
2009 Tat mRNA can be translated efficiently both in vitro and in cells, likely via an internal ribosome entry site (IRES) mechanism. Tat protein can strongly stimulate translation from its own cognate mRNA in a TAR-dependent fashion, providing a positive feedback loop to ensure sufficient Tat production early in infection. In vitro translation assays; monocistronic and dicistronic reporter RNA constructs with Tat 5'-UTR; cell-based translation assays; TAR deletion/mutation analysis Retrovirology Medium 19671151
2000 Thrombospondin-1 (TSP) binds directly to Tat protein with high affinity (Kd = 25 nM); TSP inhibits cell internalization and HIV-1 LTR trans-activating activity of extracellular Tat (ID50 = 10-30 nM), as well as Tat's mitogenic activity. TSP is ineffective once Tat has already bound to cell-surface heparan sulfate proteoglycans, and TSP prevents but does not disrupt Tat-heparin interaction in vitro. GST-Tat pulldown; Scatchard binding analysis; LTR trans-activation assays; cell internalization assays; heparin-Tat interaction competition assays FASEB journal Medium 11023976
2016 HIV-1 Tat expression in astrocytes induces lysosomal exocytosis, which is the mechanism of astrocyte-mediated Tat neurotoxicity. Tat-induced lysosomal exocytosis requires GFAP expression and is mediated through ER stress. Two-dimensional gel electrophoresis and mass spectrometry identified elevated lysosomal hydrolytic enzymes and plasma membrane-associated proteins in the conditioned medium of Tat-expressing astrocytes. 2D gel electrophoresis and mass spectrometry; lysosomal exocytosis assays; GFAP knockout/knockdown; ER stress pathway analysis; conditioned medium neurotoxicity assays The Journal of biological chemistry Medium 27609518
2020 Two-pore channels (TPCs) in endolysosomes regulate Tat escape from endolysosomes into the cytosol and subsequent LTR transactivation; pharmacological blocking or knockdown of TPCs attenuates Tat endolysosome escape and LTR transactivation. Chelating endolysosomal or cytosolic calcium also attenuates Tat escape. TRPML1 knockdown has no effect, indicating specificity for TPCs. Pharmacological TPC inhibitors; TPC and TRPML1 siRNA knockdown; calcium chelation (rhodamine-dextran for endolysosomal Ca2+, BAPTA-AM for cytosolic Ca2+); LTR transactivation reporter assays; Tat endolysosome escape imaging assays FASEB journal Medium 31950548
2006 Tat-derived peptides (but not full-length Tat protein itself) competitively and reversibly inhibit neprilysin, the major amyloid beta-peptide degrading enzyme in the brain. Both Tat peptides and Tat protein are slowly hydrolyzed by neprilysin, suggesting that proteolytic fragments accumulate and inhibit the enzyme. In vitro inhibition assays with recombinant neprilysin; kinetic analysis (competitive inhibition); comparison of Tat protein vs. Tat-derived peptides Journal of neurovirology Medium 16877296

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Tat-mediated delivery of heterologous proteins into cells. Proceedings of the National Academy of Sciences of the United States of America 1017 8290579
2000 The Tat protein export pathway. Molecular microbiology 452 10652088
2012 The twin-arginine translocation (Tat) protein export pathway. Nature reviews. Microbiology 390 22683878
1999 Tackling Tat. Journal of molecular biology 365 10550206
1999 HIV-1 tat transcriptional activity is regulated by acetylation. The EMBO journal 361 10545121
2001 TAT-mediated protein transduction into mammalian cells. Methods (San Diego, Calif.) 310 11403574
2007 TAT transduction: the molecular mechanism and therapeutic prospects. Trends in molecular medicine 284 17913584
2005 SIRT1 regulates HIV transcription via Tat deacetylation. PLoS biology 282 15719057
1998 HIV-1 Tat protein mimicry of chemokines. Proceedings of the National Academy of Sciences of the United States of America 228 9789057
1991 The HIV-1 Tat protein activates transcription from an upstream DNA-binding site: implications for Tat function. Genes & development 226 1752440
1990 Sequence-specific interaction of Tat protein and Tat peptides with the transactivation-responsive sequence element of human immunodeficiency virus type 1 in vitro. Proceedings of the National Academy of Sciences of the United States of America 207 2247474
2011 The ins and outs of HIV-1 Tat. Traffic (Copenhagen, Denmark) 195 21951552
2003 TAT peptide internalization: seeking the mechanism of entry. Current protein & peptide science 194 12678851
2003 The Tat protein translocation pathway and its role in microbial physiology. Advances in microbial physiology 192 14560665
2005 Protein targeting by the bacterial twin-arginine translocation (Tat) pathway. Current opinion in microbiology 175 15802249
1995 Structural studies of HIV-1 Tat protein. Journal of molecular biology 165 7723010
1996 Tat-SF1: cofactor for stimulation of transcriptional elongation by HIV-1 Tat. Science (New York, N.Y.) 144 8849451
1999 HIV-1 Tat-mediated activation of glycogen synthase kinase-3beta contributes to Tat-mediated neurotoxicity. Journal of neurochemistry 142 10428053
2002 Sequence and phylogenetic analyses of the twin-arginine targeting (Tat) protein export system. Archives of microbiology 141 12029389
2005 Tat gets the "green" light on transcription initiation. Retrovirology 132 16280076
1997 Tat is required for efficient HIV-1 reverse transcription. The EMBO journal 132 9135139
2009 Role of Tat protein in HIV neuropathogenesis. Neurotoxicity research 124 19526283
2002 Tat stimulates cotranscriptional capping of HIV mRNA. Molecular cell 119 12408826
2019 Presence of Tat and transactivation response element in spinal fluid despite antiretroviral therapy. AIDS (London, England) 117 31789815
2002 Transcriptional synergy between Tat and PCAF is dependent on the binding of acetylated Tat to the PCAF bromodomain. The EMBO journal 115 12032084
1993 Exogenous tat protein activates human endothelial cells. Blood 115 7693046
2004 Tat-dependent protein targeting in prokaryotes and chloroplasts. Biochimica et biophysica acta 114 15546663
2008 NMDA receptor activation by HIV-Tat protein is clade dependent. The Journal of neuroscience : the official journal of the Society for Neuroscience 111 19020013
2002 TAT protein transduction into isolated perfused hearts: TAT-apoptosis repressor with caspase recruitment domain is cardioprotective. Circulation 109 12163436
2004 Intracellular cargo delivery using tat peptide and derivatives. Medicinal research reviews 107 14595670
1999 HIV-1 Tat: coping with negative elongation factors. Current opinion in immunology 96 10448148
2005 Transcellular protein transduction using the Tat protein of HIV-1. Advanced drug delivery reviews 90 15722166
2006 TAT-BH4 and TAT-Bcl-xL peptides protect against sepsis-induced lymphocyte apoptosis in vivo. Journal of immunology (Baltimore, Md. : 1950) 88 16622015
2005 The Tat pathway in bacteria and chloroplasts (review). Molecular membrane biology 88 16092529
2016 Curcumin inhibits HIV-1 by promoting Tat protein degradation. Scientific reports 87 27283735
1992 Activation of HIV transcription by Tat. Current opinion in genetics & development 87 1638124
2003 TAT-liposomes: a novel intracellular drug carrier. Current protein & peptide science 83 12678852
2020 HIV-1 Tat: Role in Bystander Toxicity. Frontiers in cellular and infection microbiology 79 32158701
2009 Morphine enhances Tat-induced activation in murine microglia. Journal of neurovirology 77 19462331
2005 Influence of TAT-peptide polymerization on properties and transfection activity of TAT/DNA polyplexes. Journal of controlled release : official journal of the Controlled Release Society 77 15653153
2001 Pharmacokinetics and delivery of tat and tat-protein conjugates to tissues in vivo. Bioconjugate chemistry 77 11716691
1993 Tat and the HIV-1 promoter. Current opinion in cell biology 77 8352964
2013 Long-term efficient gene delivery using polyethylenimine with modified Tat peptide. Biomaterials 74 24268201
2009 Functional substitution by TAT-utrophin in dystrophin-deficient mice. PLoS medicine 73 19478831
2019 Transport of Folded Proteins by the Tat System. The protein journal 70 31401776
2013 The Tat system of Gram-positive bacteria. Biochimica et biophysica acta 70 24140208
2007 Tit-for-tat or win-stay, lose-shift? Journal of theoretical biology 70 17481667
1991 A minimal lentivirus Tat. Journal of virology 69 1658392
1999 HIV-1-trans-activating (Tat) protein: both a target and a tool in therapeutic approaches. Biochemical pharmacology 67 10535742
2010 HIV-1 Tat is unconventionally secreted through the plasma membrane. Cell biology international 63 19995346
2017 HIV, Tat and dopamine transmission. Neurobiology of disease 62 28457951
1998 The HIV-1 Tat cellular coactivator Tat-SF1 is a general transcription elongation factor. Genes & development 61 9765201
1999 The tat protein of HIV-1 induces galectin-3 expression. Glycobiology 60 10089212
2015 Mechanistic Aspects of Folded Protein Transport by the Twin Arginine Translocase (Tat). The Journal of biological chemistry 59 25975269
2006 The multiple functions of HIV-1 Tat: proliferation versus apoptosis. Frontiers in bioscience : a journal and virtual library 55 16146763
2005 TAR RNA recognition by a cyclic peptidomimetic of Tat protein. Biochemistry 55 16156649
2008 TatABC overexpression improves Corynebacterium glutamicum Tat-dependent protein secretion. Applied and environmental microbiology 54 19074606
2016 Assembling the Tat protein translocase. eLife 51 27914200
2005 HIV-1 Tat protein enhances microtubule polymerization. Retrovirology 51 15691386
2005 Decoding Tat: the biology of HIV Tat posttranslational modifications. Microbes and infection 49 16046164
1999 Tat-SF1 protein associates with RAP30 and human SPT5 proteins. Molecular and cellular biology 49 10454543
2014 Protein transport by the bacterial Tat pathway. Biochimica et biophysica acta 48 24583120
2007 TAT-Bim induces extensive apoptosis in cancer cells. Annals of surgical oncology 48 17206479
2017 HIV-1 TAT protein enhances sensitization to methamphetamine by affecting dopaminergic function. Brain, behavior, and immunity 47 28495611
2013 Synaptodendritic recovery following HIV Tat exposure: neurorestoration by phytoestrogens. Journal of neurochemistry 45 23875777
2017 USP7 deubiquitinase controls HIV-1 production by stabilizing Tat protein. The Biochemical journal 44 28280111
2006 Tat peptides inhibit neprilysin. Journal of neurovirology 44 16877296
2015 TAT Modification of Alpha-Helical Anticancer Peptides to Improve Specificity and Efficacy. PloS one 43 26405806
2010 Multiple precursor proteins bind individual Tat receptor complexes and are collectively transported. The EMBO journal 43 20339348
2009 TAT peptide and its conjugates: proteolytic stability. Bioconjugate chemistry 43 19601640
2011 Tits and bits of HIV Tat protein. Expert opinion on biological therapy 40 21204735
2008 The HIV Tat protein affects processing of ribosomal RNA precursor. BMC cell biology 40 18559082
2013 Increased excitability in tat-transgenic mice: role of tat in HIV-related neurological disorders. Neurobiology of disease 39 23454193
2010 Activation of Egr-1 expression in astrocytes by HIV-1 Tat: new insights into astrocyte-mediated Tat neurotoxicity. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 39 20414733
2009 Mechanism of HIV-1 Tat RNA translation and its activation by the Tat protein. Retrovirology 39 19671151
2016 HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity. The Journal of biological chemistry 38 27609518
2003 Tat-neutralizing antibodies in vaccinated macaques. Journal of virology 38 12584340
2010 Improved Tat-mediated plasmid DNA transfer by fusion to LK15 peptide. Journal of controlled release : official journal of the Controlled Release Society 37 20060860
1991 RNA binding by the tat and rev proteins of HIV-1. Biochimie 37 1903308
2020 Two-pore channels regulate Tat endolysosome escape and Tat-mediated HIV-1 LTR transactivation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 36 31950548
2014 Effects of HIV-1 Tat on enteric neuropathogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 36 25339738
1998 Transcriptional control: Tat cofactors and transcriptional elongation. Current biology : CB 35 9651670
2018 TAT-Gap19 and Carbenoxolone Alleviate Liver Fibrosis in Mice. International journal of molecular sciences 34 29534516
2006 Purification of TAT-C3 exoenzyme. Methods in enzymology 34 16472655
2005 Inhibition of Tat activity by the HEXIM1 protein. Retrovirology 34 15992410
2005 Discoveries of Tat-TAR interaction inhibitors for HIV-1. Current drug targets. Infectious disorders 34 16535863
2015 Delayed Administration of Tat-HA-NR2B9c Promotes Recovery After Stroke in Rats. Stroke 33 25851770
2000 Blocking HIV replication by targeting Tat protein. Chemistry & biology 30 10980447
2005 HIV-1 Tat interacts with LIS1 protein. Retrovirology 29 15698475
1998 Tat, Tat-associated kinase, and transcription. Journal of biomedical science 29 9570510
2004 Factors controlling the efficiency of Tat-mediated plasmid DNA transfer. Journal of drug targeting 28 15203910
2014 PACAP27 is protective against tat-induced neurotoxicity. Journal of molecular neuroscience : MN 27 24696163
2010 The Tat Protein Export Pathway. EcoSal Plus 27 26443788
2009 Differential Interactions between Tat-specific redox enzyme peptides and their chaperones. Journal of bacteriology 27 19151138
2005 Expression of tumor-associated trypsinogens (TAT-1 and TAT-2) in prostate cancer. The Prostate 27 15651064
2005 TAT-GDNF in neurodegeneration and ischemic stroke. CNS drug reviews 26 16614736
1995 Neurotoxic mechanisms of transactivating protein Tat of Maedi-Visna virus. Neuroscience letters 26 8552302
2000 Thrombospondin-1/HIV-1 tat protein interaction: modulation of the biological activity of extracellular Tat. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25 11023976
2020 The Plant Mitochondrial TAT Pathway Is Essential for Complex III Biogenesis. Current biology : CB 24 32084398
2002 Transduction of TAT fusion proteins into osteoclasts and osteoblasts. Biochemical and biophysical research communications 24 12445831

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