HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription.
Recruitment of the P-TEFb kinase by HIV-1 Tat to the viral promoter triggers the phosphorylation and escape of RNA polymerase II from promoter-proximal pausing. It is unclear, however, if Tat recruits additional host factors that further stimulate HIV-1 transcription. Using a sequential affinity-purification scheme, we have identified human transcription factors/coactivators AFF4, ENL, AF9, and elongation factor ELL2 as components of the Tat-P-TEFb complex. Through the bridging functions of Tat and AFF4, P-TEFb and ELL2 combine to form a bifunctional elongation complex that greatly activates HIV-1 transcription. Without Tat, AFF4 can mediate the ELL2-P-TEFb interaction, albeit inefficiently. Tat overcomes this limitation by bringing more ELL2 to P-TEFb and stabilizing ELL2 in a process that requires active P-TEFb. The ability of Tat to enable two different classes of elongation factors to cooperate and coordinate their actions on the same polymerase enzyme explains why Tat is such a powerful activator of HIV-1 transcription.
He
Nanhai
N
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Liu
Min
M
Hsu
Joanne
J
Xue
Yuhua
Y
Chou
Seemay
S
Burlingame
Alma
A
Krogan
Nevan J
NJ
Alber
Tom
T
Zhou
Qiang
Q
D001665:Binding Sites; D002460:Cell Line; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D046912:Multiprotein Complexes; D009687:Nuclear Proteins / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D034622:RNA Interference; D012367:RNA, Viral / Q000096:biosynthesis*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D035602:Transcriptional Elongation Factors / Q000378:metabolism; D014162:Transfection; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
C471348:AFF4 protein, human; C090862:ELL protein, human; C447613:ELL2 protein, human; C489901:MLLT3 protein, human; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D061988:Proteasome Inhibitors; D012367:RNA, Viral; D012097:Repressor Proteins; D035602:Transcriptional Elongation Factors; D054322:tat Gene Products, Human Immunodeficiency Virus; D042925:Positive Transcriptional Elongation Factor B; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9; D046988:Proteasome Endopeptidase Complex
Mol Cell. 2008 Mar 14;29(5):588-99
18249148
Genes Dev. 1998 Nov 15;12(22):3512-27
9832504
Science. 2008 Mar 28;319(5871):1791-2
18369138
Mol Cell. 2006 Aug 4;23(3):297-305
16885020
Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14535-40
10588740
Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3639-43
9108030
Genes Dev. 1997 Oct 15;11(20):2633-44
9334326
PLoS Biol. 2009 Nov;7(11):e1000249
19956800
EMBO J. 1995 Jan 16;14(2):321-8
7835343
Nature. 2001 Nov 15;414(6861):317-22
11713532
Nat Immunol. 2009 Oct;10(10):1102-9
19749764
Cancer Res. 2008 Dec 15;68(24):10024-7
19074864
Blood. 2007 Dec 15;110(13):4445-54
17855633
Mol Cell. 2005 Aug 19;19(4):535-45
16109377
Mol Cell. 2010 Feb 12;37(3):429-37
20159561
J Biomed Sci. 2002 May-Jun;9(3):234-45
12065898
Cell. 1998 Feb 20;92(4):451-62
9491887
Cancer Cell. 2010 Feb 17;17(2):198-212
20153263
J Immunol. 2007 Dec 1;179(11):7663-73
18025212
J Biol Chem. 2001 Aug 24;276(34):31793-9
11431468
Hum Mol Genet. 2007 Jan 1;16(1):92-106
17135274
Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12110-4
7991593
Oncogene. 2000 Jan 20;19(3):373-9
10656684
Mol Cell. 2005 Aug 19;19(4):523-34
16109376
Science. 1996 Mar 29;271(5257):1873-6
8596958
Genes Dev. 2004 Oct 15;18(20):2437-68
15489290
Nature. 2001 Nov 15;414(6861):322-5
11713533
EMBO J. 1998 Jul 1;17(13):3681-91
9649438
Mol Cell. 2007 Jul 20;27(2):262-74
17643375
Mol Genet Genomics. 2007 Feb;277(2):101-14
17001490
Mol Cell. 2010 May 14;38(3):439-51
20471949
Mol Cell. 2003 Oct;12(4):971-82
14580347
Microbiol Mol Biol Rev. 2006 Sep;70(3):646-59
16959964
Genes Dev. 1997 Oct 15;11(20):2622-32
9334325