UVDDB p127-binding modulates activities and intracellular distribution of hepatitis B virus X protein.
Mammalian hepatitis B viruses encode a unique regulatory protein termed X, which is essential for infection and likely plays a role in the carcinogenic process associated with hepadnaviral infection. Among the numerous properties ascribed to X protein, two have been widely documented: promiscuous transcriptional transactivation and proapoptosis. However, full understanding of the mechanisms underlying these activities requires the identification of the genuine X partners among the multiple X-binding host proteins. Here we show that (i) mutations in X protein, which markedly alter affinity for the host protein UVDDBp127, inactivate both transactivation and proapoptosis; (ii) ectopic fusion of a functional UVDDB-binding domain to a deficient binding X mutant restored its activity; (iii) in contrast to the loss-of-binding mutants, a mutant with a strong gain-of-binding exerted trans-dominant negative effects on wt X activity and localized in the nucleus and (iv) increase in intracellular UVDDB concentration enhanced both wt X-mediated transactivation and apoptosis. Taken together, our data provide strong evidence for a common upstream step in X mode of action, consisting of its productive interaction with UVDDB, via a structurally and functionally autonomous module. In addition, they underscore a nuclear location step of the viral protein that depends on its ability to bind UVDDB.
Sitterlin
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D
Institut Pasteur, Unité de recombinaison et expression génétique (INSERM U163), 28 rue du Dr Roux 75724 Paris Cedex 15, France.
Bergametti
F
F
Transy
C
C
D017209:Apoptosis / Q000502:physiology; D001692:Biological Transport; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D017919:Hepatitis B Virus, Woodchuck / Q000737:chemistry; D006801:Humans; D009154:Mutation; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D054334:Viral Regulatory and Accessory Proteins
C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein