UVDDB p127-binding modulates activities and intracellular distribution of hepatitis B virus X protein

Oncogene. 2000 Sep 7;19(38):4417-26. doi: 10.1038/sj.onc.1203771.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology
  • Biological Transport
  • Cell Line
  • Cell Nucleus / metabolism
  • Cell Survival
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Hepatitis B Virus, Woodchuck / chemistry
  • Humans
  • Mutation
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Trans-Activators / metabolism*
  • Transcriptional Activation

Substances

  • DDB1 protein, human
  • DNA-Binding Proteins
  • Recombinant Proteins
  • Trans-Activators
  • hepatitis B virus X protein