ID A0A888WB74_9HIV1 Unreviewed; 101 AA. AC A0A888WB74; DT 29-SEP-2021, integrated into UniProtKB/TrEMBL. DT 29-SEP-2021, sequence version 1. DT 12-OCT-2022, entry version 5. DE RecName: Full=Protein Tat {ECO:0000256|ARBA:ARBA00022376, ECO:0000256|HAMAP-Rule:MF_04079}; DE AltName: Full=Transactivating regulatory protein {ECO:0000256|HAMAP-Rule:MF_04079}; GN Name=tat {ECO:0000256|HAMAP-Rule:MF_04079, GN ECO:0000313|EMBL:QRC49190.1}; OS Human immunodeficiency virus 1. OC Viruses; Riboviria; Pararnavirae; Artverviricota; Revtraviricetes; OC Ortervirales; Retroviridae; Orthoretrovirinae; Lentivirus. OX NCBI_TaxID=11676 {ECO:0000313|EMBL:QRC49190.1}; OH NCBI_TaxID=9606; Homo sapiens (Human). RN [1] {ECO:0000313|EMBL:QRC49190.1} RP NUCLEOTIDE SEQUENCE. RC STRAIN=LNA819_6_39 {ECO:0000313|EMBL:QRC49190.1}; RA Gao Y., He S., Tian W., Li D., An M., Zhao B., Ding H., Xu J., Chu Z., RA Shang H., Han X.; RL Submitted (DEC-2020) to the EMBL/GenBank/DDBJ databases. CC -!- FUNCTION: Extracellular circulating Tat can be endocytosed by CC surrounding uninfected cells via the binding to several surface CC receptors such as CD26, CXCR4, heparan sulfate proteoglycans (HSPG) or CC LDLR. Neurons are rarely infected, but they internalize Tat via their CC LDLR. Through its interaction with nuclear HATs, Tat is potentially CC able to control the acetylation-dependent cellular gene expression. CC Modulates the expression of many cellular genes involved in cell CC survival, proliferation or in coding for cytokines or cytokine CC receptors. Tat plays a role in T-cell and neurons apoptosis. Tat CC induced neurotoxicity and apoptosis probably contribute to neuroAIDS. CC Circulating Tat also acts as a chemokine-like and/or growth factor-like CC molecule that binds to specific receptors on the surface of the cells, CC affecting many cellular pathways. In the vascular system, Tat binds to CC ITGAV/ITGB3 and ITGA5/ITGB1 integrins dimers at the surface of CC endothelial cells and competes with bFGF for heparin-binding sites, CC leading to an excess of soluble bFGF. {ECO:0000256|HAMAP- CC Rule:MF_04079}. CC -!- FUNCTION: Nuclear transcriptional activator of viral gene expression, CC that is essential for viral transcription from the LTR promoter and CC replication. Acts as a sequence-specific molecular adapter, directing CC components of the cellular transcription machinery to the viral RNA to CC promote processive transcription elongation by the RNA polymerase II CC (RNA pol II) complex, thereby increasing the level of full-length CC transcripts. In the absence of Tat, the RNA Pol II generates short or CC non-processive transcripts that terminate at approximately 60 bp from CC the initiation site. Tat associates with the CCNT1/cyclin-T1 component CC of the P-TEFb complex (CDK9 and CCNT1), which promotes RNA chain CC elongation. This binding increases Tat's affinity for a hairpin CC structure at the 5'-end of all nascent viral mRNAs referred to as the CC transactivation responsive RNA element (TAR RNA) and allows Tat/P-TEFb CC complex to bind cooperatively to TAR RNA. The CDK9 component of P-TEFb CC and other Tat-activated kinases hyperphosphorylate the C-terminus of CC RNA Pol II that becomes stabilized and much more processive. Other CC factors such as HTATSF1/Tat-SF1, SUPT5H/SPT5, and HTATIP2 are also CC important for Tat's function. Besides its effect on RNA Pol II CC processivity, Tat induces chromatin remodeling of proviral genes by CC recruiting the histone acetyltransferases (HATs) CREBBP, EP300 and PCAF CC to the chromatin. This also contributes to the increase in proviral CC transcription rate, especially when the provirus integrates in CC transcriptionally silent region of the host genome. To ensure maximal CC activation of the LTR, Tat mediates nuclear translocation of NF-kappa-B CC by interacting with host RELA. Through its interaction with host TBP, CC Tat may also modulate transcription initiation. Tat can reactivate a CC latently infected cell by penetrating in it and transactivating its LTR CC promoter. In the cytoplasm, Tat is thought to act as a translational CC activator of HIV-1 mRNAs. {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- SUBUNIT: Interacts with host CCNT1. Associates with the P-TEFb complex CC composed at least of Tat, P-TEFb (CDK9 and CCNT1), TAR RNA, RNA Pol II. CC Recruits the HATs CREBBP, TAF1/TFIID, EP300, PCAF and GCN5L2. Interacts CC with host KAT5/Tip60; this interaction targets the latter to CC degradation. Interacts with the host deacetylase SIRT1. Interacts with CC host capping enzyme RNGTT; this interaction stimulates RNGTT. Binds to CC host KDR, and to the host integrins ITGAV/ITGB3 and ITGA5/ITGB1. CC Interacts with host KPNB1/importin beta-1 without previous binding to CC KPNA1/importin alpha-1. Interacts with EIF2AK2. Interacts with host CC nucleosome assembly protein NAP1L1; this interaction may be required CC for the transport of Tat within the nucleus, since the two proteins CC interact at the nuclear rim. Interacts with host C1QBP/SF2P32; this CC interaction involves lysine-acetylated Tat. Interacts with the host CC chemokine receptors CCR2, CCR3 and CXCR4. Interacts with host CC DPP4/CD26; this interaction may trigger an anti-proliferative effect. CC Interacts with host LDLR. Interacts with the host extracellular matrix CC metalloproteinase MMP1. Interacts with host PRMT6; this interaction CC mediates Tat's methylation. Interacts with, and is ubiquitinated by CC MDM2/Hdm2. Interacts with host PSMC3 and HTATIP2. Interacts with STAB1; CC this interaction may overcome SATB1-mediated repression of IL2 and CC IL2RA (interleukin) in T cells by binding to the same domain than CC HDAC1. Interacts (when acetylated) with human CDK13, thereby increasing CC HIV-1 mRNA splicing and promoting the production of the doubly spliced CC HIV-1 protein Nef.Interacts with host TBP; this interaction modulates CC the activity of transcriptional pre-initiation complex. Interacts with CC host RELA. {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- SUBCELLULAR LOCATION: Host nucleus, host nucleolus {ECO:0000256|HAMAP- CC Rule:MF_04079}. Host cytoplasm {ECO:0000256|HAMAP-Rule:MF_04079}. CC Secreted {ECO:0000256|HAMAP-Rule:MF_04079}. Note=Probably localizes to CC both nuclear and nucleolar compartments. Nuclear localization is CC mediated through the interaction of the nuclear localization signal CC with importin KPNB1. Secretion occurs through a Golgi-independent CC pathway. Tat is released from infected cells to the extracellular space CC where it remains associated to the cell membrane, or is secreted into CC the cerebrospinal fluid and sera. Extracellular Tat can be endocytosed CC by surrounding uninfected cells via binding to several receptors CC depending on the cell type. {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- DOMAIN: The Arg-rich RNA-binding region binds the TAR RNA. This region CC also mediates the nuclear localization through direct binding to KPNB1 CC and is involved in Tat's transfer across cell membranes (protein CC transduction). The same region is required for the interaction with CC EP300, PCAF, EIF2AK2 and KDR. {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- DOMAIN: The Cys-rich region may bind 2 zinc ions. This region is CC involved in binding to KAT5. {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- DOMAIN: The cell attachment site mediates the interaction with CC ITGAV/ITGB3 and ITGA5/ITGB1 integrins, leading to vascular cell CC migration and invasion. This interaction also provides endothelial CC cells with the adhesion signal they require to grow in response to CC mitogens. {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- DOMAIN: The transactivation domain mediates the interaction with CCNT1, CC GCN5L2, and MDM2. {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- PTM: Acetylation by EP300, CREBBP, GCN5L2/GCN5 and PCAF regulates the CC transactivation activity of Tat. EP300-mediated acetylation of Lys-50 CC promotes dissociation of Tat from the TAR RNA through the competitive CC binding to PCAF's bromodomain. In addition, the non-acetylated Tat's N- CC terminus can also interact with PCAF. PCAF-mediated acetylation of Lys- CC 28 enhances Tat's binding to CCNT1. Lys-50 is deacetylated by SIRT1. CC {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- PTM: Asymmetrical arginine methylation by host PRMT6 seems to diminish CC the transactivation capacity of Tat and affects the interaction with CC host CCNT1. {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- PTM: Phosphorylated by EIF2AK2 on serine and threonine residues CC adjacent to the basic region important for TAR RNA binding and CC function. Phosphorylation of Tat by EIF2AK2 is dependent on the prior CC activation of EIF2AK2 by dsRNA. {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- PTM: Polyubiquitination by host MDM2 does not target Tat to CC degradation, but activates its transactivation function and fosters CC interaction with CCNT1 and TAR RNA. {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- MISCELLANEOUS: HIV-1 lineages are divided in three main groups, M (for CC Major), O (for Outlier), and N (for New, or Non-M, Non-O). The vast CC majority of strains found worldwide belong to the group M. Group O CC seems to be endemic to and largely confined to Cameroon and neighboring CC countries in West Central Africa, where these viruses represent a small CC minority of HIV-1 strains. The group N is represented by a limited CC number of isolates from Cameroonian persons. The group M is further CC subdivided in 9 clades or subtypes (A to D, F to H, J and K). CC {ECO:0000256|HAMAP-Rule:MF_04079}. CC -!- SIMILARITY: Belongs to the lentiviruses Tat family. CC {ECO:0000256|ARBA:ARBA00009398, ECO:0000256|HAMAP-Rule:MF_04079, CC ECO:0000256|RuleBase:RU003311}. CC -!- CAUTION: Lacks conserved residue(s) required for the propagation of CC feature annotation. {ECO:0000256|HAMAP-Rule:MF_04079}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; MW344805; QRC49190.1; -; Genomic_RNA. DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell. DR GO; GO:0030430; C:host cell cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0044196; C:host cell nucleolus; IEA:UniProtKB-SubCell. DR GO; GO:0042805; F:actinin binding; IEA:UniProtKB-UniRule. DR GO; GO:0030332; F:cyclin binding; IEA:UniProtKB-UniRule. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-UniRule. DR GO; GO:0019904; F:protein domain specific binding; IEA:UniProtKB-UniRule. DR GO; GO:0001070; F:RNA-binding transcription regulator activity; IEA:UniProtKB-UniRule. DR GO; GO:1990970; F:trans-activation response element binding; IEA:UniProtKB-UniRule. DR GO; GO:0039525; P:modulation by virus of host chromatin organization; IEA:UniProtKB-UniRule. DR GO; GO:0039586; P:modulation by virus of host PP1 activity; IEA:UniProtKB-UniRule. DR GO; GO:0010801; P:negative regulation of peptidyl-threonine phosphorylation; IEA:UniProtKB-UniRule. DR GO; GO:0032968; P:positive regulation of transcription elongation by RNA polymerase II; IEA:UniProtKB-UniRule. DR GO; GO:0050434; P:positive regulation of viral transcription; IEA:UniProtKB-UniRule. DR GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; IEA:UniProtKB-UniRule. DR Gene3D; 4.10.20.10; -; 1. DR HAMAP; MF_04079; HIV_TAT; 1. DR InterPro; IPR001831; IV_Tat. DR InterPro; IPR036963; Tat_dom_sf. DR Pfam; PF00539; Tat; 1. DR PRINTS; PR00055; HIVTATDOMAIN. PE 3: Inferred from homology; KW Acetylation {ECO:0000256|HAMAP-Rule:MF_04079}; KW Activator {ECO:0000256|ARBA:ARBA00023159, ECO:0000256|HAMAP-Rule:MF_04079}; KW Apoptosis {ECO:0000256|HAMAP-Rule:MF_04079}; KW Host cytoplasm {ECO:0000256|HAMAP-Rule:MF_04079}; KW Host nucleus {ECO:0000256|ARBA:ARBA00022562, ECO:0000256|HAMAP- KW Rule:MF_04079}; KW Host-virus interaction {ECO:0000256|ARBA:ARBA00022581, ECO:0000256|HAMAP- KW Rule:MF_04079}; KW Inhibition of host innate immune response by virus {ECO:0000256|HAMAP- KW Rule:MF_04079}; KW Inhibition of host interferon signaling pathway by virus KW {ECO:0000256|HAMAP-Rule:MF_04079}; KW Isopeptide bond {ECO:0000256|HAMAP-Rule:MF_04079}; KW Metal-binding {ECO:0000256|HAMAP-Rule:MF_04079}; KW Methylation {ECO:0000256|HAMAP-Rule:MF_04079}; KW Modulation of host chromatin by virus {ECO:0000256|HAMAP-Rule:MF_04079}; KW Modulation of host PP1 activity by virus {ECO:0000256|HAMAP-Rule:MF_04079}; KW Phosphoprotein {ECO:0000256|HAMAP-Rule:MF_04079}; KW RNA-binding {ECO:0000256|ARBA:ARBA00022884, ECO:0000256|HAMAP- KW Rule:MF_04079}; Secreted {ECO:0000256|HAMAP-Rule:MF_04079}; KW Transcription {ECO:0000256|ARBA:ARBA00023163, ECO:0000256|HAMAP- KW Rule:MF_04079}; KW Transcription regulation {ECO:0000256|ARBA:ARBA00023015, ECO:0000256|HAMAP- KW Rule:MF_04079}; Ubl conjugation {ECO:0000256|HAMAP-Rule:MF_04079}; KW Viral immunoevasion {ECO:0000256|HAMAP-Rule:MF_04079}; KW Zinc {ECO:0000256|HAMAP-Rule:MF_04079}. FT REGION 1..48 FT /note="Transactivation" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" FT REGION 1..24 FT /note="Interaction with human CREBBP" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" FT REGION 1..20 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 22..37 FT /note="Cysteine-rich" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" FT REGION 38..48 FT /note="Core" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" FT REGION 48..101 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 49..86 FT /note="Interaction with the host capping enzyme RNGTT" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" FT MOTIF 49..57 FT /note="Nuclear localization signal, RNA-binding (TAR), and FT protein transduction" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" FT COMPBIAS 63..82 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 83..101 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 22 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" FT BINDING 25 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" FT BINDING 27 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" FT BINDING 30 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" FT BINDING 33 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" FT BINDING 34 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" FT BINDING 37 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" FT SITE 11 FT /note="Essential for Tat translocation through the FT endosomal membrane" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" FT MOD_RES 28 FT /note="N6-acetyllysine; by host PCAF" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" FT MOD_RES 51 FT /note="N6-acetyllysine; by host EP300 and GCN5L2" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" FT MOD_RES 52 FT /note="Asymmetric dimethylarginine; by host PRMT6" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" FT MOD_RES 53 FT /note="Asymmetric dimethylarginine; by host PRMT6" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" FT CROSSLNK 71 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000256|HAMAP-Rule:MF_04079" SQ SEQUENCE 101 AA; 11500 MW; 007F688552AE0991 CRC64; MEPVDPNLEP WKHPGSQPKT ACTNCYCKKC CFHCQVCFTK KGLGIFYGRR KRRPRRRTPQ SSEDHQNSIS KQPLSTSRGN QTGQKESKEK VASKAETDPC D //