Multifaceted Activities of the HIV-1 Transactivator of Transcription, Tat

human immunodeficiency virus, type 1 long terminal repeat RNA polymerase II TATA-binding protein Tat-associated kinase carboxyl-terminal domain Tat-associated histone acetyltransferase TBP-associated factor Human immunodeficiency virus, type 1 (HIV-1)1 is the etiological agent for the acquired immunodeficiency syndrome (AIDS). HIV-1 is a retrovirus that encodes a small nuclear transcriptional activator protein, Tat (Fig. 1). In vivo, Tat is required for virus replication and is conserved in the genomes of all primate lentiviruses (1Myers G. Korber B.T. Foley B.T. Jeang K-T. Mellors J.W. Wain-Hobson S. Human Retroviruses and AIDS: A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences. Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM1996: III-11-III-26Google Scholar). Over the past decade, the transcriptional function(s) of Tat (reviewed in detail several years ago (2Jones K.A. Peterlin B.M. Annu. Rev. Biochem. 1994; 63: 717-743Crossref PubMed Scopus (559) Google Scholar)) has been intensely investigated. It has become clear that a primary role for Tat is in regulating productive and processive transcription from the HIV-1 long terminal repeat (LTR). Tat also has other activities; some are consistent with that of a secreted growth factor (3Chang H.K. Gallo R.C. Ensoli B.J. J. Biomed. Sci. 1995; 2: 189-202Crossref PubMed Scopus (91) Google Scholar, 4Trinh D.P. Brown K.M. Jeang K.T. Biochem. Biophys. Res. Commun. 1999; 256: 299-306Crossref PubMed Scopus (29) Google Scholar, 5Albini A. Ferrini S. Benelli R. Sforzini S. Giunciuglio D. Aluigi M.G. Proudfoot A.E. Alouani S. Wells T.N. Mariani G. Rabin R.L. Farber J.M. Noonan D.M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 13153-13158Crossref PubMed Scopus (245) Google Scholar) and a potentiator of reverse transcription (6Harrich D. Ulich C. Garcia-Martinez L.F. Gaynor R. EMBO J. 1997; 16: 1224-1235Crossref PubMed Scopus (124) Google Scholar). Here we review recent insights into the multifaceted activities of Tat. Tat is a transcriptional activator that binds to a short nascent stem-bulge-loop leader RNA, TAR (trans-activation responsive (7Berkhout B. Silverman R.H. Jeang K.T. Cell. 1989; 59: 273-282Abstract Full Text PDF PubMed Scopus (513) Google Scholar, 8Dingwall C. Ernberg I. Gait M.J. Green S.M. Heaphy S. Karn J. Lowe A.D. Singh M. Skinner M.A. EMBO J. 1990; 9: 4145-4153Crossref PubMed Scopus (340) Google Scholar, 9Cordingley M.G. La Femina R.L. Callahan P.L. Condra J.H. Sardana V.V. Graham D.J. Nguyen T.M. Le Grow K. Gotlib L. Schlabach A.J. Colonno R.J. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 8985-8989Crossref PubMed Scopus (176) Google Scholar, 10Calnan B.J. Biancalana S. Hudson D. Frankel A.D. Genes Dev. 1991; 5: 201-210Crossref PubMed Scopus (292) Google Scholar)), for its activity. The 101-amino acid Tat protein, with residues 1–72 encoded by a first exon and residues 73–101 encoded by a second exon, can be arbitrarily considered as containing several "domains" (11Kuppuswamy M. Subramanian T. Srinivasan A. Chinnadurai G. Nucleic Acids Res. 1989; 17: 3551-3561Crossref PubMed Scopus (208) Google Scholar) (Fig. 1). Of interest, it should be noted that whereas an 86-amino acid form of Tat, which exists for a few laboratory-passaged virus strains (e.g. LAI, HXB2, pNL4–3) (Fig. 1), has been frequently used; this version represents a truncated and not naturally full-length protein. Indeed, a single nucleotide change in LAI, HXB2, and/or pNL4–3 at putative residue 87 unmasks in these respective genomes the conserved 101 amino acids (Fig. 1) of Tat that are found in most in vivo isolates of virus. This suggests that the premature termination codon that exists in laboratory isolates at position 87 conceivably arose artifactually during tissue culture passaging (12Neuveut C. Jeang K.T. J. Virol. 1996; 70: 5572-5581Crossref PubMed Google Scholar). Thus, that more than 90% of the more than 100 extant independently characterized HIV-1 Tat proteins maintain the 101 (and not the 86) amino acid configuration (1Myers G. Korber B.T. Foley B.T. Jeang K-T. Mellors J.W. Wain-Hobson S. Human Retroviruses and AIDS: A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences. Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM1996: III-11-III-26Google Scholar) is consistent with this interpretation. Hence, although residues 87–101 of Tat might not contribute greatly to the ex vivo propagation of HIV-1, their conservation in viruses that replicate in vivoprovides a good indication of their biological importance. In this regard, the second coding exon of Tat, which in many studies has been frequently not considered, has been shown to be significant in several biological assays (13Viglianti G. Mullins J.I. J. Virol. 1988; 62: 4523-4532Crossref PubMed Google Scholar, 14Tong-Starksen S. Baur A. Lu X.B. Peck E. Peterlin B.M. Virology. 1993; 195: 826-830Crossref PubMed Scopus (23) Google Scholar, 15Jeang K.-T. Berkhout B. Dropulic B. J. Biol. Chem. 1993; 268: 24940-24949Abstract Full Text PDF PubMed Google Scholar, 16Howcroft T.K. Strebel K. Martin M.A. Singer D.S. Science. 1993; 260: 1320-1323Crossref PubMed Scopus (200) Google Scholar, 17Verhoef K. Bauer M. Meyerhans A. Berkhout B. AIDS Res. Hum. Retroviruses. 1998; 14: 1553-1559Crossref PubMed Scopus (40) Google Scholar, 18Xiao H. Neuveut C. Benkirane M. Jeang K.T. Biochem. Biophys. Res. Commun. 1998; 244: 384-389Crossref PubMed Scopus (43) Google Scholar, 19Ott M. Emiliani S. Van Lint C. Herbein G. Lovett J. Chirmule N. McCloskey T. Pahwa S. Verdin E. Science. 1997; 275: 1481-1485Crossref PubMed Scopus (187) Google Scholar). Over the past decade, a detailed structure-function analysis of Tat has emerged, in part through the generation of an extensive collection of point mutants (Table I) produced from 11 laboratories (11Kuppuswamy M. Subramanian T. Srinivasan A. Chinnadurai G. Nucleic Acids Res. 1989; 17: 3551-3561Crossref PubMed Scopus (208) Google Scholar, 12Neuveut C. Jeang K.T. J. Virol. 1996; 70: 5572-5581Crossref PubMed Google Scholar, 20Garcia J.A. Harrich D. Pearson L. Misuyasu R. Gaynor R. EMBO J. 1988; 7: 3143-3147Crossref PubMed Scopus (139) Google Scholar, 21Sadaie M.R. Rappaport J. Benter T. Josephs S.F. Willis R. Wong-Staal F. Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 9224-9228Crossref PubMed Scopus (62) Google Scholar, 22Ruben S. Perkins A. Purcell R. Joung K. Sia R. Burghoff R. Haseltine W.A. Rosen C.A. J. Virol. 1989; 63: 1-8Crossref PubMed Google Scholar, 23Hauber J. Malim M.H. Cullen B.R. J. Virol. 1989; 63: 1181-1187Crossref PubMed Google Scholar, 24Meyerhans A. Cheynier R. Albert J. Seth M. Kwok S. Sninsky J. Morfeldt-Manson L. Asjo B. Wain-Hobson S. Cell. 1989; 58: 901-910Abstract Full Text PDF PubMed Scopus (512) Google Scholar, 25Rice A.P. Carlotti F. J. Virol. 1990; 64: 1864-1868Crossref PubMed Google Scholar, 26Rice A.P. Carlotti F. J. Virol. 1990; 64: 6018-6026Crossref PubMed Google Scholar, 27Siderovski D.P. Matsuyama T. Frigerio E. Chui S. Min X. Erfle H. Sumner-Smith M. Barnett R.W. Mak T.W. Nucleic Acids Res. 1992; 20: 5311-5320Crossref PubMed Scopus (12) Google Scholar, 28Verhoef K. Berkhout B. J. Virol. 1999; 73: 2781-2789Crossref PubMed Google Scholar, 29Ulich C. Dunne A. Parry E. Hooker C.W. Gaynor R.B. Harrich D. J. Virol. 1999; 73: 2499-2508Crossref PubMed Google Scholar). From these mutants, one notes that single residue changes in domain 1 of Tat (amino acids 1–20) are well tolerated. By contrast, changes in six of the seven highly conserved cysteines in amino acids 21–40 (Fig. 1, domain2) abolish function (see Table I). Domain 3 (amino acids 41–48) contains a common RKGLGI motif found in HIV-1, HIV-2, and SIV Tat. Amino acids 1–48 together circumscribe a minimal activation domain for HIV-1 Tat (30Carroll R. Martarano L. Derse D. J. Virol. 1991; 65: 3460-3467Crossref PubMed Google Scholar, 31Derse D. Carvalho M. Carroll R. Peterlin B.M. J. Virol. 1991; 65: 7012-7015Crossref PubMed Google Scholar).Table IPoint mutations in TatAmino acid changesAmino acid changesFromaLetter(s) indicates original amino acid(s). Number indicates position of amino acid in Tat.TobLetter(s) indicates the resulting amino acid(s).Activitiesc++, >50% wild type; +, >10% wild type activity; +/− or −, ∼10% or 50% wild type; +, >10% wild type activity; +/− or −, ∼10% or 50% wild type; +, >10% wild type activity; +/− or −, ∼10% or <10% wild type activity.d Measurement of contribution by Tat to reverse transcription (29Ulich C. Dunne A. Parry E. Hooker C.W. Gaynor R.B. Harrich D. J. Virol. 1999; 73: 2499-2508Crossref PubMed Google Scholar).e Measurement is based not upon trans-activation of a reporter plasmid but on delayed replication of an HIV-1 molecular clone in T-cell lines (12Neuveut C. Jeang K.T. J. Virol. 1996; 70: 5572-5581Crossref PubMed Google Scholar, 28Verhoef K. Berkhout B. J. Virol. 1999; 73: 2781-2789Crossref PubMed Google Scholar).f Different results reported for the same mutation from Refs.11Kuppuswamy M. Subramanian T. Srinivasan A. Chinnadurai G. Nucleic Acids Res. 1989; 17: 3551-3561Crossref PubMed Scopus (208) Google Scholar and 24Meyerhans A. Cheynier R. Albert J. Seth M. Kwok S. Sninsky J. Morfeldt-Manson L. Asjo B. Wain-Hobson S. Cell. 1989; 58: 901-910Abstract Full Text PDF PubMed Scopus (512) Google Scholar.g Amino acids beyond position 59 completely changed.h Frameshift of amino acids beyond position 81. Open table in a new tab Perhaps the best studied region of Tat resides in amino acids 49–72 (domain 4), which contain a basic RKKRRQRRR motif. This peptide motif confers TAR RNA binding properties to Tat (32Dingwall C. Ernberg I. Gait M.J. Green S.M. Heaphy S. Karn J. Lowe A.D. Singh M. Skinner M.A. Vallerio R. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 6925-6929Crossref PubMed Scopus (402) Google Scholar, 33Roy S. Delling U. Chen C.-H. Rosen C.A. Sonenberg N. Genes Dev. 1990; 4: 1365-1373Crossref PubMed Scopus (326) Google Scholar, 34Weeks K.M. Crothers D.M. Cell. 1991; 66: 577-588Abstract Full Text PDF PubMed Scopus (302) Google Scholar, 35Chang Y.N. Jeang K.T. Nucleic Acids Res. 1992; 20: 5465-5472Crossref PubMed Scopus (31) Google Scholar) and is important for nuclear localization of the protein (22Ruben S. Perkins A. Purcell R. Joung K. Sia R. Burghoff R. Haseltine W.A. Rosen C.A. J. Virol. 1989; 63: 1-8Crossref PubMed Google Scholar, 23Hauber J. Malim M.H. Cullen B.R. J. Virol. 1989; 63: 1181-1187Crossref PubMed Google Scholar) and uptake of Tat by cells (3Chang H.K. Gallo R.C. Ensoli B.J. J. Biomed. Sci. 1995; 2: 189-202Crossref PubMed Scopus (91) Google Scholar). For association with TAR, the short basic motif contributes importantly to affinity but dictates insufficiently specificity of binding. Flanking amino acids outside this basic domain influence significantly the specificity of Tat-TAR interaction (36Churcher M.J. Lamont C. Hamy F. Dingwall C. Green S.M. Lowe A. Butler P.J.C. Gait M.J. Karn J. J. Mol. Biol. 1993; 230: 90-110Crossref PubMed Scopus (261) Google Scholar, 37Luo Y. Peterlin B.M. J. Virol. 1993; 67: 3441-3445Crossref PubMed Google Scholar). A recent detailed review of Tat-TAR RNA interaction is available elsewhere (38Rana T.M. Jeang K.-T. Arch. Biochem. Biophys. 1999; 365: 175-185Crossref PubMed Scopus (162) Google Scholar). Transcription from the HIV-1 LTR is several hundred-fold higher in the presence of Tat than in its absence. Thus, Tat must resolve a rate-limiting step at this promoter. Optimal Tat action requires, in addition to TAR RNA, basal (TATA and initiator sequence) and upstream promoter elements (i.e. Sp1) (39Berkhout B. Jeang K.T. J. Virol. 1992; 66: 139-149Crossref PubMed Google Scholar) (Fig.2). Recent experimental findings have added to our understanding of the mechanism(s) through which Tat acts through these elements. In considering Tat action, one understands that two operationally defined events occur for each round of transcription at virtually all promoters. These are: (i) recruitment of an RNA polymerase II (RNAP II) complex to the promoter and (ii) the escape of that complex from the promoter into productive elongation. A typicalrole proposed for transcriptional activator proteins is that of facilitating a rate-limiting step in the recruitment of TBP-bound RNAP II to the promoter (40Chatterjee S. Struhl K. Nature. 1995; 374: 820-822Crossref PubMed Scopus (167) Google Scholar, 41Xiao H. Friesen J.D. Lis J.T. Mol. Cell. Biol. 1995; 15: 5757-5761Crossref PubMed Scopus (102) Google Scholar). Although Tat is not a typical activator protein, it does possess the capacity to bind directly several general transcription factors including TFIID (42Kashanchi F. Piras G. Radonovich M.F. Duvall J.F. Roeder R. Brady J.N. Nature. 1994; 367: 295-299Crossref PubMed Scopus (229) Google Scholar), TFIIB (43Veschambre P. Roisin A. Jalinot P. J. Gen. Virol. 1997; 78: 2235-2245Crossref PubMed Scopus (27) Google Scholar), TFIIH (44Parada C.A. Roeder R.G. Nature. 1996; 384: 375-377Crossref PubMed Scopus (237) Google Scholar), and RNAP II (45Wu-Baer F. Sigman D. Gaynor R.B. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7153-7157Crossref PubMed Scopus (60) Google Scholar). Thus, an attractively simple mechanism of how Tat might accelerate the rate of transcription from the HIV-1 LTR would be if it increased the recruitment of TBP/RNAP II to the viral promoter. This hypothesis was directly examined; and in such a study, it was found that Tat unlikely functions at recruiting TBP/RNAP II to the LTR promoter. Indeed, the rate-limiting event(s) resolved by Tat occurs at a step(s) post-TBP recruitment to the HIV-1 TATAA promoter (46Xiao H. Lis J.T. Jeang K.T. Mol. Cell. Biol. 1997; 17: 6898-6905Crossref PubMed Scopus (52) Google Scholar). What might be the "post-recruitment" step(s) influenced by Tat? Events that ensue after the docking of TBP/RNAP II at the promoter range, among others, from the consummation of a competent initiation complex to the clearance of such a complex from the promoter to the transit of cleared RNAP IIs into productive elongation. Because Tat function requires the presynthesis of at least the first 44 nascent nucleotides of TAR RNA (7Berkhout B. Silverman R.H. Jeang K.T. Cell. 1989; 59: 273-282Abstract Full Text PDF PubMed Scopus (513) Google Scholar), activation cannot occur until the initiated RNAP II has proceeded beyond this position (47Jeang K.-T. Berkhout B. J. Biol. Chem. 1992; 267: 17891-17899Abstract Full Text PDF PubMed Google Scholar). This scenario, which is very much compatible with Tat overcoming a "block" to transcription (44Parada C.A. Roeder R.G. 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Jeang K.T. J. Virol. 1998; PubMed Google Scholar) that some Tat might not be to an RNAP II and from the promoter Gait M.J. Karn J. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: PubMed Scopus (91) Google Scholar, M.J. Karn J. EMBO J. 1997; 16: Scopus Google Scholar). In of Tat with K.T. R. A. H. J. Virol. 1993; 67: PubMed Google Scholar, R.F. Neuveut C. Jeang K.T. J. Virol. 1998; PubMed Google Scholar) that some Tat protein could be at a promoter Tat could influence transcriptional in a to L. D. Annu. Rev. Biochem. 1995; 64: PubMed Scopus Google Scholar). It to be directly such a function could for Tat. HIV-1 has an transcriptional that is not found for For large of its HIV-1, other exists as E. P. Van Lint C. EMBO J. 1993; 12: PubMed Scopus Google Scholar) in In its the HIV-1 LTR is with histone proteins in a In this regard, by RNAP II to these is a step that is not well by the transcription assays for Tat recent have this from an these a role for a histone acetyltransferase in transcriptional of RNAP II to was shown to be by the and/or J. Virol. 1998; PubMed Google Scholar, M. R.F. H. V.V. Y. Jeang K.T. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, G. M. M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: PubMed Scopus Google Scholar, J.D. Brown T.K. J. A. P.A. L. Y. Singer D.S. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: PubMed Scopus Google Scholar) such as from the have of or more By contrast, the HIV-1 is than in For of viral the HIV-1 must functions to encoded the genomes of A of is that each HIV-1 might have been to Indeed, based on Tat was shown to have activities in addition to its transcriptional function for the viral LTR A. R. J. Jeang K.T. EMBO J. 1994; PubMed Scopus Google Scholar). of these functions have been from several laboratories and the activation of M. Emiliani S. Van Lint C. Herbein G. Lovett J. Chirmule N. McCloskey T. Pahwa S. Verdin E. Science. 1997; 275: 1481-1485Crossref PubMed Scopus (187) Google Scholar), the of D.J. C. Science. 1995; 268: PubMed Scopus Google Scholar), and the of such as that for K. R. M. Los M. EMBO J. 1995; 14: PubMed Scopus Google Scholar). Tat also has functions consistent with an A. Ferrini S. Benelli R. Sforzini S. Giunciuglio D. Aluigi M.G. Proudfoot A.E. Alouani S. Wells T.N. Mariani G. Rabin R.L. Farber J.M. Noonan D.M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 13153-13158Crossref PubMed Scopus (245) Google Scholar) and/or growth factor D.P. Brown K.M. Jeang K.T. Biochem. Biophys. Res. Commun. 1999; 256: 299-306Crossref PubMed Scopus (29) Google Scholar). is that Tat might through H. Neuveut C. Benkirane M. Jeang K.T. Biochem. Biophys. Res. Commun. 1998; 244: 384-389Crossref PubMed Scopus (43) Google Scholar) and/or reverse transcription J.A. Harrich D. Pearson L. Misuyasu R. Gaynor R. EMBO J. 1988; 7: 3143-3147Crossref PubMed Scopus (139) Google Scholar) of these activities for Tat have not been studied in their to be in on Tat the have important biological and Tat as a of an protein that functions in eukaryotic transcription. in the transcriptional of Tat, new of general of transcriptional elongation and processivity and activation of promoters From the we have how this protein can with RNAP II and histone in from the LTR promoter. In studies to Tat has an important for how highly proteins can be into cells L. S.F. 1999; 5: PubMed Scopus Google and in to AIDS is that HIV-1 J.M. Y. C. C. D. D. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus (60) Google Scholar) and a for a viral G. 1996; 2: PubMed Scopus Google Scholar) are by the biological functions of the Tat protein. Indeed, although we have much of the transcriptional properties of Tat, much more to be