ID   TAT_HV1ET               Reviewed;          42 AA.
AC   Q75005;
DT   11-JUL-2006, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1996, sequence version 1.
DT   27-MAR-2024, entry version 110.
DE   RecName: Full=Protein Tat;
DE   AltName: Full=Transactivating regulatory protein;
OS   Human immunodeficiency virus type 1 group M subtype C (isolate ETH2220)
OS   (HIV-1).
OC   Viruses; Riboviria; Pararnavirae; Artverviricota; Revtraviricetes;
OC   Ortervirales; Retroviridae; Orthoretrovirinae; Lentivirus;
OC   Human immunodeficiency virus 1.
OX   NCBI_TaxID=388796;
OH   NCBI_TaxID=9606; Homo sapiens (Human).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=8891112; DOI=10.1089/aid.1996.12.1329;
RA   Salminen M.O., Johansson B., Sonnerborg A., Ayehunie S., Gotte D.,
RA   Leinikki P., Burke D.S., McCutchan F.E.;
RT   "Full-length sequence of an ethiopian human immunodeficiency virus type 1
RT   (HIV-1) isolate of genetic subtype C.";
RL   AIDS Res. Hum. Retroviruses 12:1329-1339(1996).
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: Transcriptional activator that increases RNA Pol II
CC       processivity, thereby increasing the level of full-length viral
CC       transcripts. Recognizes a hairpin structure at the 5'-LTR of the
CC       nascent viral mRNAs referred to as the transactivation responsive RNA
CC       element (TAR) and recruits the cyclin T1-CDK9 complex (P-TEFb complex)
CC       that will in turn hyperphosphorylate the RNA polymerase II to allow
CC       efficient elongation. The CDK9 component of P-TEFb and other Tat-
CC       activated kinases hyperphosphorylate the C-terminus of RNA Pol II that
CC       becomes stabilized and much more processive. Other factors such as
CC       HTATSF1/Tat-SF1, SUPT5H/SPT5, and HTATIP2 are also important for Tat's
CC       function. Besides its effect on RNA Pol II processivity, Tat induces
CC       chromatin remodeling of proviral genes by recruiting the histone
CC       acetyltransferases (HATs) CREBBP, EP300 and PCAF to the chromatin. This
CC       also contributes to the increase in proviral transcription rate,
CC       especially when the provirus integrates in transcriptionally silent
CC       region of the host genome. To ensure maximal activation of the LTR, Tat
CC       mediates nuclear translocation of NF-kappa-B by interacting with host
CC       RELA. Through its interaction with host TBP, Tat may also modulate
CC       transcription initiation. Tat can reactivate a latently infected cell
CC       by 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. {ECO:0000250|UniProtKB:P04608}.
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:0000250|UniProtKB:P04608}.
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. Interacts with host PLSCR1; this interaction negatively
CC       regulates Tat transactivation activity by altering its subcellular
CC       distribution. {ECO:0000255|HAMAP-Rule:MF_04079}.
CC   -!- SUBCELLULAR LOCATION: Host nucleus, host nucleolus
CC       {ECO:0000250|UniProtKB:P04608}. Host cytoplasm
CC       {ECO:0000250|UniProtKB:P04608}. Secreted
CC       {ECO:0000250|UniProtKB:P04608}. Note=Probably localizes to both nuclear
CC       and nucleolar compartments. Nuclear localization is mediated through
CC       the interaction of the nuclear localization signal with importin KPNB1.
CC       Secretion occurs through a Golgi-independent pathway. Tat is released
CC       from infected cells to the extracellular space where it remains
CC       associated to the cell membrane, or is secreted into the cerebrospinal
CC       fluid and sera. Extracellular Tat can be endocytosed by surrounding
CC       uninfected cells via binding to several receptors depending on the cell
CC       type. {ECO:0000250|UniProtKB:P04608}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=Long;
CC         IsoId=Q75005-1; Sequence=Displayed;
CC       Name=Short;
CC         IsoId=Q75005-2; Sequence=Not described;
CC   -!- DOMAIN: The transactivation domain mediates the interaction with CCNT1,
CC       GCN5L2, and MDM2. {ECO:0000250|UniProtKB:P04610}.
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:0000250|UniProtKB:P04610}.
CC   -!- DOMAIN: The Cys-rich region may bind 2 zinc ions. This region is
CC       involved in binding to KAT5. {ECO:0000250|UniProtKB:P04610}.
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:0000250|UniProtKB:P04610}.
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:0000250|UniProtKB:P04608}.
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|UniProtKB:P04608}.
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:0000250|UniProtKB:P04608}.
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: This truncated variant has a premature stop codon. It
CC       may have arose as a consequence of tissue culture passaging.
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; U46016; AAB36504.1; -; Genomic_DNA.
DR   SMR; Q75005; -.
DR   Proteomes; UP000007694; Segment.
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:0004865; F:protein serine/threonine phosphatase inhibitor activity; 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:0039525; P:modulation by virus of host chromatin organization; IEA:UniProtKB-KW.
DR   GO; GO:0050434; P:positive regulation of viral transcription; IEA:InterPro.
DR   GO; GO:0039606; P:suppression by virus of host translation initiation; IEA:UniProtKB-KW.
DR   GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; IEA:UniProtKB-KW.
DR   Gene3D; 4.10.20.10; Tat domain; 1.
DR   InterPro; IPR001831; IV_Tat.
DR   InterPro; IPR036963; Tat_dom_sf.
DR   Pfam; PF00539; Tat; 1.
PE   3: Inferred from homology;
KW   Acetylation; Activator; AIDS; Alternative splicing; Apoptosis;
KW   Host cytoplasm; Host nucleus; Host-virus interaction;
KW   Inhibition of host innate immune response by virus;
KW   Inhibition of host interferon signaling pathway by virus;
KW   Interferon antiviral system evasion; Metal-binding; Methylation;
KW   Modulation of host chromatin by virus;
KW   Modulation of host PP1 activity by virus; Phosphoprotein; RNA-binding;
KW   Secreted; Transcription; Transcription regulation; Ubl conjugation;
KW   Viral immunoevasion; Zinc.
FT   CHAIN           1..42
FT                   /note="Protein Tat"
FT                   /id="PRO_0000244851"
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   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"
SQ   SEQUENCE   42 AA;  4786 MW;  583F4346E07C007B CRC64;
     MEPVDPNLEP WNHPGSQPKT ACNQCYCKKC SYHCLVCFLT KA
//