Acetylation of HIV-1 integrase by p300 regulates viral integration.
Integration of HIV-1 into the human genome, which is catalyzed by the viral protein integrase (IN), preferentially occurs near transcriptionally active genes. Here we show that p300, a cellular acetyltransferase that regulates chromatin conformation through the acetylation of histones, also acetylates IN and controls its activity. We have found that p300 directly binds IN both in vitro and in the cells, as also specifically demonstrated by fluorescence resonance energy transfer technique analysis. This interaction results in the acetylation of three specific lysines (K264, K266, K273) in the carboxy-terminus of IN, a region that is required for DNA binding. Acetylation increases IN affinity to DNA, and promotes the DNA strand transfer activity of the protein. In the context of the viral replication cycle, point mutations in the IN acetylation sites abolish virus replication by specifically impairing its integration capacity. This is the first demonstration that HIV-1 IN activity is specifically regulated by post-translational modification.
Cereseto
Anna
A
Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy. a.cereseto@sns.it
Manganaro
Lara
L
Gutierrez
Maria Ines
MI
Terreni
Mariaelena
M
Fittipaldi
Antonio
A
Lusic
Marina
M
Marcello
Alessandro
A
Giacca
Mauro
M
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D000595:Amino Acid Sequence; D002384:Catalysis; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism*; D051548:Histone Acetyltransferases; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008969:Molecular Sequence Data; D017354:Point Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000378:metabolism*; D016662:Virus Integration / Q000502:physiology*; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D019427:HIV Integrase; D051548:Histone Acetyltransferases; D008239:Lysine; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor