HIV-1 Tat targets Tip60 to impair the apoptotic cell response to genotoxic stresses.
HIV-1 transactivator Tat uses cellular acetylation signalling by targeting several cellular histone acetyltransferases (HAT) to optimize its various functions. Although Tip60 was the first HAT identified to interact with Tat, the biological significance of this interaction has remained obscure. We had previously shown that Tat represses Tip60 HAT activity. Here, a new mechanism of Tip60 neutralization by Tat is described, where Tip60 is identified as a substrate for the newly reported p300/CBP-associated E4-type ubiquitin-ligase activity, and Tat uses this mechanism to induce the polyubiquitination and degradation of Tip60. Tip60 targeting by Tat results in a dramatic impairment of the Tip60-dependent apoptotic cell response to DNA damage. These data reveal yet unknown strategies developed by HIV-1 to increase cell resistance to genotoxic stresses and show a role of Tat as a modulator of cellular protein ubiquitination.
Laboratoire de Biologie Moléculaire et Cellulaire de la Différenciation, INSERM U309, Equipe chromatine et expression des gènes, Institut Albert Bonniot, Faculté de Médecine, Domaine de la Merci, La Tronche, France.
Edwige
E
Col
Cécile
C
Caron
Christine
C
Chable-Bessia
Gaelle
G
Legube
Sylvie
S
Gazzeri
Yasuhiko
Y
Komatsu
Minoru
M
Yoshida
Monsef
M
Benkirane
Didier
D
Trouche
Saadi
S
Khochbin
D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D004249:DNA Damage / Q000502:physiology*; D015696:Gene Products, tat / Q000378:metabolism* / Q000502:physiology*; D015497:HIV-1 / Q000378:metabolism*; D051548:Histone Acetyltransferases; D006801:Humans; D019169:Jurkat Cells; D000074443:Lysine Acetyltransferase 5; D009687:Nuclear Proteins / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D009687:Nuclear Proteins; D015534:Trans-Activators; D054322:tat Gene Products, Human Immunodeficiency Virus; D025821:Polyubiquitin; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5