TAT_HV1B5
ID TAT_HV1B5 Reviewed; 58 AA.
AC P04612;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
DT 13-AUG-1987, sequence version 1.
DT 29-SEP-2021, entry version 112.
DE RecName: Full=Protein Tat;
DE AltName: Full=Transactivating regulatory protein;
DE Flags: Fragment;
OS Human immunodeficiency virus type 1 group M subtype B (isolate BH5)
OS (HIV-1).
OC Viruses; Riboviria; Pararnavirae; Artverviricota; Revtraviricetes;
OC Ortervirales; Retroviridae; Orthoretrovirinae; Lentivirus.
OX NCBI_TaxID=11682;
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX PubMed=2578615; DOI=10.1038/313277a0;
RA Ratner L., Haseltine W.A., Patarca R., Livak K.J., Starcich B.R.,
RA Josephs S.F., Doran E.R., Rafalski J.A., Whitehorn E.A., Baumeister K.,
RA Ivanoff L., Petteway S.R. Jr., Pearson M.L., Lautenberger J.A., Papas T.S.,
RA Ghrayeb J., Chang N.T., Gallo R.C., Wong-Staal F.;
RT "Complete nucleotide sequence of the AIDS virus, HTLV-III.";
RL Nature 313:277-284(1985).
RN [2]
RP REVIEW, AND ALTERNATIVE SPLICING.
RX PubMed=16046164; DOI=10.1016/j.micinf.2005.06.003;
RA Hetzer C., Dormeyer W., Schnolzer M., Ott M.;
RT "Decoding Tat: the biology of HIV Tat posttranslational modifications.";
RL Microbes Infect. 7:1364-1369(2005).
RN [3]
RP REVIEW.
RX PubMed=16146763; DOI=10.2741/1829;
RA Peruzzi F.;
RT "The multiple functions of HIV-1 Tat: proliferation versus apoptosis.";
RL Front. Biosci. 11:708-717(2006).
RN [4]
RP REVIEW.
RX PubMed=16697675; DOI=10.1016/j.micinf.2005.11.014;
RA King J.E., Eugenin E.A., Buckner C.M., Berman J.W.;
RT "HIV tat and neurotoxicity.";
RL Microbes Infect. 8:1347-1357(2006).
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-
CC B. In this purpose, it activates EIF2AK2/PKR which, in turns, may
CC phosphorylate and target to degradation the inhibitor IkappaB-alpha
CC which normally retains NF-kappa-B in the cytoplasm of unstimulated
CC cells. Through its interaction with TBP, Tat may be involved in
CC transcription initiation as well. Interacts with the cellular capping
CC enzyme RNGTT to mediate co-transcriptional capping of viral mRNAs. Tat
CC protein exerts as well a positive feedback on the translation of its
CC cognate mRNA. Tat can reactivate a latently infected cell by
CC penetrating in it and transactivating its LTR promoter. In the
CC cytoplasm, Tat is thought to act as a translational activator of HIV-1
CC mRNAs (By similarity). {ECO:0000250}.
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. Endosomal low pH allows Tat to cross the endosome membrane to
CC enter the cytosol and eventually further translocate into the nucleus,
CC thereby inducing severe cell dysfunctions ranging from cell activation
CC to cell death. Through its interaction with nuclear HATs, Tat is
CC potentially able to control the acetylation-dependent cellular gene
CC expression. Tat seems to inhibit the HAT activity of KAT5/Tip60 and
CC TAF1, and consequently modify the expression of specific cellular
CC genes. Modulates the expression of many cellular genes involved in cell
CC survival, proliferation or in coding for cytokines (such as IL10) or
CC cytokine receptors. May be involved in the derepression of host
CC interleukin IL2 expression. Mediates the activation of cyclin-dependent
CC kinases and dysregulation of microtubule network. Tat plays a role in
CC T-cell and neurons apoptosis. Tat induced neurotoxicity and apoptosis
CC probably contribute to neuroAIDS. Host extracellular matrix
CC metalloproteinase MMP1 cleaves Tat and decreases Tat's mediated
CC neurotoxicity. Circulating Tat also acts as a chemokine-like and/or
CC growth factor-like molecule that binds to specific receptors on the
CC surface of the cells, affecting many cellular pathways. In the vascular
CC system, Tat binds to ITGAV/ITGB3 and ITGA5/ITGB1 integrins dimers at
CC the surface of endothelial cells and competes with bFGF for heparin-
CC binding sites, leading to an excess of soluble bFGF. Binds to
CC KDR/VEGFR-2. All these Tat-mediated effects enhance angiogenesis in
CC Kaposi's sarcoma lesions (By similarity). {ECO:0000250}.
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 on Lys-50 and Lys-51) with human
CC CDK13, thereby increasing HIV-1 mRNA splicing and promoting the
CC production of the doubly spliced HIV-1 protein Nef (By similarity).
CC {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Host nucleus, host nucleolus. Host cytoplasm.
CC Secreted. Note=Probably localizes to both nuclear and nucleolar
CC compartments. Nuclear localization is mediated through the interaction
CC of the nuclear localization signal with importin KPNB1. Secretion
CC occurs through a Golgi-independent pathway. Tat is released from
CC infected cells to the extracellular space where it remains associated
CC to the cell membrane, or is secreted into the cerebrospinal fluid and
CC sera. Extracellular Tat can be endocytosed by surrounding uninfected
CC cells via binding to several receptors depending on the cell type (By
CC similarity). {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Long;
CC IsoId=P04612-1; Sequence=Displayed;
CC Name=Short;
CC IsoId=P04612-2; Sequence=Not described;
CC -!- DOMAIN: The transactivation domain mediates the interaction with CCNT1,
CC GCN5L2, and MDM2. {ECO:0000250}.
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 (By similarity). {ECO:0000250}.
CC -!- DOMAIN: The Cys-rich region may bind 2 zinc ions (Potential). This
CC region is involved in binding to KAT5 (By similarity). {ECO:0000250,
CC ECO:0000305}.
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 (By similarity). {ECO:0000250}.
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 (By
CC similarity). {ECO:0000250}.
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 (By similarity). {ECO:0000250}.
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:0000250}.
CC -!- PTM: Polyubiquitination by MDM2 does not target Tat to degradation, but
CC activates its transactivation function and fosters interaction with
CC CCNT1 and TAR RNA. {ECO:0000250}.
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 -!- MISCELLANEOUS: [Isoform Short]: Expressed in the late stage of the
CC infection cycle, when unspliced viral RNAs are exported to the
CC cytoplasm by the viral Rev protein. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the lentiviruses Tat family. {ECO:0000305}.
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DR EMBL; K02012; AAA44656.1; -; Genomic_RNA.
DR SMR; P04612; -.
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:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR GO; GO:0001070; F:RNA-binding transcription regulator activity; IEA:InterPro.
DR GO; GO:0050434; P:positive regulation of viral transcription; IEA:InterPro.
DR Gene3D; 4.10.20.10; -; 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; Activator; AIDS; Alternative splicing; Apoptosis;
KW Host cytoplasm; Host nucleus; Host-virus interaction; Metal-binding;
KW Methylation; Phosphoprotein; RNA-binding; Secreted; Transcription;
KW Transcription regulation; Ubl conjugation; Zinc.
FT CHAIN 1..>58
FT /note="Protein Tat"
FT /id="PRO_0000085343"
FT REGION 1..48
FT /note="Transactivation"
FT /evidence="ECO:0000250"
FT REGION 1..24
FT /note="Interaction with human CREBBP"
FT /evidence="ECO:0000250"
FT REGION 22..37
FT /note="Cysteine-rich"
FT /evidence="ECO:0000250"
FT REGION 38..48
FT /note="Core"
FT /evidence="ECO:0000250"
FT REGION 49..>58
FT /note="Interaction with the host capping enzyme RNGTT"
FT /evidence="ECO:0000250"
FT MOTIF 49..57
FT /note="Nuclear localization signal, RNA-binding (TAR), and
FT protein transduction"
FT /evidence="ECO:0000250"
FT SITE 11
FT /note="Essential for Tat's translocation through the
FT endosomal membrane"
FT /evidence="ECO:0000250"
FT MOD_RES 28
FT /note="N6-acetyllysine; by host PCAF"
FT /evidence="ECO:0000250"
FT MOD_RES 50
FT /note="N6-acetyllysine; by host EP300 and GCN5L2"
FT /evidence="ECO:0000250"
FT MOD_RES 51
FT /note="N6-acetyllysine; by host EP300 and GCN5L2"
FT /evidence="ECO:0000250"
FT MOD_RES 52
FT /note="Asymmetric dimethylarginine; by host PRMT6"
FT /evidence="ECO:0000250"
FT MOD_RES 53
FT /note="Asymmetric dimethylarginine; by host PRMT6"
FT /evidence="ECO:0000250"
FT NON_TER 58
SQ SEQUENCE 58 AA; 6800 MW; E36C21F8FFD813E3 CRC64;
MEPVDPRLEP WKHPGSQPKT ACTTCYCKKC CFHCQVCFIT KALGISYGRK KRRQRRRA
