HIV1 Vpr arrests the cell cycle by recruiting DCAF1/VprBP, a receptor of the Cul4-DDB1 ubiquitin ligase.
How the HIV1 Vpr protein initiates the host cell response leading to cell cycle arrest in G(2) has remained unknown. Here, we show that recruitment of DCAF1/VprBP by Vpr is essential for its cytostatic activity, which can be abolished either by single mutations of Vpr that impair DCAF1 binding, or by siRNA-mediated silencing of DCAF1. Furthermore, DCAF1 bridges Vpr to DDB1, a core subunit of Cul4 ubiquitin ligases. Altogether these results point to a mechanism where Vpr triggers G(2) arrest by hijacking the Cul4/DDB1(DCAF1) ubiquitin ligase. We further show that, Vpx, a non-cytostatic Vpr-related protein acquired by HIV2 and SIV, also binds DCAF1 through a conserved motif. Thus, Vpr from HIV1 and Vpx from SIV recruit DCAF1 with different physiological outcomes for the host cell. This in turn suggests that both proteins have evolved to preserve interaction with the same Cul4 ubiquitin ligase while diverging in the recognition of host substrates targeted for proteasomal degradation.
Le Rouzic
Erwann
E
Institut Cochin, Département Maladies Infectieuses, Inserm, CNRS, Université Paris 5, Paris, France.
Belaïdouni
Nadia
N
Estrabaud
Emilie
E
Morel
Marina
M
Rain
Jean-Christophe
JC
Transy
Catherine
C
Margottin-Goguet
Florence
F
D000595:Amino Acid Sequence; D002453:Cell Cycle / Q000502:physiology*; D044842:Cullin Proteins / Q000378:metabolism* / Q000502:physiology; D003603:Cytotoxins / Q000502:physiology / Q000633:toxicity; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D016336:Gene Products, vpr / Q000502:physiology* / Q000633:toxicity; D015497:HIV-1 / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D021381:Protein Transport / Q000502:physiology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism* / Q000502:physiology; D054325:vpr Gene Products, Human Immunodeficiency Virus
C114234:CUL4A protein, human; D044842:Cullin Proteins; D003603:Cytotoxins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; D016336:Gene Products, vpr; D054325:vpr Gene Products, Human Immunodeficiency Virus; D044767:Ubiquitin-Protein Ligases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases