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Annotation rule MF_04079
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General rule information [?]

Accession MF_04079
Dates 29-MAY-2017 (Created)
20-NOV-2019 (Last updated, Version 8)
Name HIV_TAT
Scope
Viruses; Lentivirus
Template P04608 (TAT_HV1H2)

Propagated annotation [?]


Identifier, protein and gene names [?]

Identifier
TAT
Protein name
RecName: Full=Protein Tat;
AltName: Full=Transactivating regulatory protein;
Gene name
tat

Comments [?]

Function Nuclear transcriptional activator of viral gene expression, that is essential for viral transcription from the LTR promoter and replication. Acts as a sequence-specific molecular adapter, directing components of the cellular transcription machinery to the viral RNA to promote processive transcription elongation by the RNA polymerase II (RNA pol II) complex, thereby increasing the level of full-length transcripts. In the absence of Tat, the RNA Pol II generates short or non-processive transcripts that terminate at approximately 60 bp from the initiation site. Tat associates with the CCNT1/cyclin-T1 component of the P-TEFb complex (CDK9 and CCNT1), which promotes RNA chain elongation. This binding increases Tat's affinity for a hairpin structure at the 5'-end of all nascent viral mRNAs referred to as the transactivation responsive RNA element (TAR RNA) and allows Tat/P-TEFb complex to bind cooperatively to TAR RNA. The CDK9 component of P-TEFb and other Tat-activated kinases hyperphosphorylate the C-terminus of RNA Pol II that becomes stabilized and much more processive. Other factors such as HTATSF1/Tat-SF1, SUPT5H/SPT5, and HTATIP2 are also important for Tat's function. Besides its effect on RNA Pol II processivity, Tat induces chromatin remodeling of proviral genes by recruiting the histone acetyltransferases (HATs) CREBBP, EP300 and PCAF to the chromatin. This also contributes to the increase in proviral transcription rate, especially when the provirus integrates in transcriptionally silent region of the host genome. To ensure maximal activation of the LTR, Tat mediates nuclear translocation of NF-kappa-B by interacting with host RELA. Through its interaction with host TBP, Tat may also modulate transcription initiation. Tat can reactivate a latently infected cell by penetrating in it and transactivating its LTR promoter. In the cytoplasm, Tat is thought to act as a translational activator of HIV-1 mRNAs.
Extracellular circulating Tat can be endocytosed by surrounding uninfected cells via the binding to several surface receptors such as CD26, CXCR4, heparan sulfate proteoglycans (HSPG) or LDLR. Neurons are rarely infected, but they internalize Tat via their LDLR. Through its interaction with nuclear HATs, Tat is potentially able to control the acetylation-dependent cellular gene expression. Modulates the expression of many cellular genes involved in cell survival, proliferation or in coding for cytokines or cytokine receptors. Tat plays a role in T-cell and neurons apoptosis. Tat induced neurotoxicity and apoptosis probably contribute to neuroAIDS. Circulating Tat also acts as a chemokine-like and/or growth factor-like molecule that binds to specific receptors on the surface of the cells, affecting many cellular pathways. In the vascular system, Tat binds to ITGAV/ITGB3 and ITGA5/ITGB1 integrins dimers at the surface of endothelial cells and competes with bFGF for heparin-binding sites, leading to an excess of soluble bFGF.
Subunit Interacts with host CCNT1. Associates with the P-TEFb complex composed at least of Tat, P-TEFb (CDK9 and CCNT1), TAR RNA, RNA Pol II. Recruits the HATs CREBBP, TAF1/TFIID, EP300, PCAF and GCN5L2. Interacts with host KAT5/Tip60; this interaction targets the latter to degradation. Interacts with the host deacetylase SIRT1. Interacts with host capping enzyme RNGTT; this interaction stimulates RNGTT. Binds to host KDR, and to the host integrins ITGAV/ITGB3 and ITGA5/ITGB1. Interacts with host KPNB1/importin beta-1 without previous binding to KPNA1/importin alpha-1. Interacts with EIF2AK2. Interacts with host nucleosome assembly protein NAP1L1; this interaction may be required for the transport of Tat within the nucleus, since the two proteins interact at the nuclear rim. Interacts with host C1QBP/SF2P32; this interaction involves lysine-acetylated Tat. Interacts with the host chemokine receptors CCR2, CCR3 and CXCR4. Interacts with host DPP4/CD26; this interaction may trigger an anti-proliferative effect. Interacts with host LDLR. Interacts with the host extracellular matrix metalloproteinase MMP1. Interacts with host PRMT6; this interaction mediates Tat's methylation. Interacts with, and is ubiquitinated by MDM2/Hdm2. Interacts with host PSMC3 and HTATIP2. Interacts with STAB1; this interaction may overcome SATB1-mediated repression of IL2 and IL2RA (interleukin) in T cells by binding to the same domain than HDAC1. Interacts (when acetylated) with human CDK13, thereby increasing HIV-1 mRNA splicing and promoting the production of the doubly spliced HIV-1 protein Nef.Interacts with host TBP; this interaction modulates the activity of transcriptional pre-initiation complex. Interacts with host RELA.
Subcellular location Host nucleus, host nucleolus. Host cytoplasm. Secreted. Note=Probably localizes to both nuclear and nucleolar compartments. Nuclear localization is mediated through the interaction of the nuclear localization signal with importin KPNB1. Secretion occurs through a Golgi-independent pathway. Tat is released from infected cells to the extracellular space where it remains associated to the cell membrane, or is secreted into the cerebrospinal fluid and sera. Extracellular Tat can be endocytosed by surrounding uninfected cells via binding to several receptors depending on the cell type.
Domain The transactivation domain mediates the interaction with CCNT1, GCN5L2, and MDM2.
The Arg-rich RNA-binding region binds the TAR RNA. This region also mediates the nuclear localization through direct binding to KPNB1 and is involved in Tat's transfer across cell membranes (protein transduction). The same region is required for the interaction with EP300, PCAF, EIF2AK2 and KDR.
The Cys-rich region may bind 2 zinc ions. This region is involved in binding to KAT5.
The cell attachment site mediates the interaction with ITGAV/ITGB3 and ITGA5/ITGB1 integrins, leading to vascular cell migration and invasion. This interaction also provides endothelial cells with the adhesion signal they require to grow in response to mitogens.
Ptm Acetylation by EP300, CREBBP, GCN5L2/GCN5 and PCAF regulates the transactivation activity of Tat. EP300-mediated acetylation of Lys-50 promotes dissociation of Tat from the TAR RNA through the competitive binding to PCAF's bromodomain. In addition, the non-acetylated Tat's N-terminus can also interact with PCAF. PCAF-mediated acetylation of Lys-28 enhances Tat's binding to CCNT1. Lys-50 is deacetylated by SIRT1.
Phosphorylated by EIF2AK2 on serine and threonine residues adjacent to the basic region important for TAR RNA binding and function. Phosphorylation of Tat by EIF2AK2 is dependent on the prior activation of EIF2AK2 by dsRNA.
Asymmetrical arginine methylation by host PRMT6 seems to diminish the transactivation capacity of Tat and affects the interaction with host CCNT1.
Polyubiquitination by host MDM2 does not target Tat to degradation, but activates its transactivation function and fosters interaction with CCNT1 and TAR RNA.
Miscellaneous HIV-1 lineages are divided in three main groups, M (for Major), O (for Outlier), and N (for New, or Non-M, Non-O). The vast majority of strains found worldwide belong to the group M. Group O seems to be endemic to and largely confined to Cameroon and neighboring countries in West Central Africa, where these viruses represent a small minority of HIV-1 strains. The group N is represented by a limited number of isolates from Cameroonian persons. The group M is further subdivided in 9 clades or subtypes (A to D, F to H, J and K).
Similarity Belongs to the lentiviruses Tat family.

Keywords [?]


Gene Ontology [?]

GO:0005576; Cellular component: extracellular region.
GO:0030430; Cellular component: host cell cytoplasm.
GO:0044196; Cellular component: host cell nucleolus.
GO:0042025; Cellular component: host cell nucleus.
GO:0042805; Molecular function: actinin binding.
GO:0030332; Molecular function: cyclin binding.
GO:0046872; Molecular function: metal ion binding.
GO:0019904; Molecular function: protein domain specific binding.
GO:0001070; Molecular function: RNA-binding transcription regulator activity.
GO:1990970; Molecular function: trans-activation response element binding.
GO:0039525; Biological process: modulation by virus of host chromatin organization.
GO:0039586; Biological process: modulation by virus of host PP1 activity.
GO:0010801; Biological process: negative regulation of peptidyl-threonine phosphorylation.
GO:0032968; Biological process: positive regulation of transcription elongation from RNA polymerase II promoter.
GO:0050434; Biological process: positive regulation of viral transcription.
GO:0039502; Biological process: suppression by virus of host type I interferon-mediated signaling pathway.
GO:0006351; Biological process: transcription, DNA-templated.

Cross-references [?]

Pfam PF00539; Tat; 1;
PRINTS PR00055; HIVTATDOMAIN; 1;

Features [?]

From: TAT_HV1H2 (P04608)
Key     From     To       Description   Tag   Condition   FTGroup
REGION     1     48       Transactivation        
REGION     1     24       Interaction with human CREBBP        
REGION     22     37       Cysteine-rich        
REGION     38     48       Core        
REGION     49     86       Interaction with the host capping enzyme RNGTT        
MOTIF     49     57       Nuclear localization signal, RNA-binding (TAR), and protein transduction        
MOTIF     78     80       Cell attachment site     R-G-D  
METAL     22     22       Zinc 1     C  
METAL     25     25       Zinc 2     C  
METAL     27     27       Zinc 2     C  
METAL     30     30       Zinc 2     C  
METAL     33     33       Zinc 1; via pros nitrogen     H  
METAL     34     34       Zinc 1     C  
METAL     37     37       Zinc 1     C  
SITE     11     11       Essential for Tat translocation through the endosomal membrane     W  
MOD_RES     28     28       N6-acetyllysine; by host PCAF     K  
MOD_RES     50     50       N6-acetyllysine; by host EP300 and GCN5L2     K  
MOD_RES     51     51       N6-acetyllysine; by host EP300 and GCN5L2     K  
MOD_RES     52     52       Asymmetric dimethylarginine; by host PRMT6     R  
MOD_RES     53     53       Asymmetric dimethylarginine; by host PRMT6     R  
CROSSLNK     71     71       Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)     K  

Additional information [?]

Size range 86-136 amino acids
Related rules None
Fusion None