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Interaction with Ppil3 leads to the cytoplasmic localization of Apoptin in tumor cells

De-Hua Huo1, Li-Na Yi, Jine Yang

  • 1The Key Laboratory of Gene Engineering of Ministry of Education, School of Life Sciences, Sun Yat-Sen (Zhongshan) University, 135th Xin-Gang-Xi Road, Guangzhou 510275, PR China.

Biochemical and Biophysical Research Communications
|May 14, 2008
PubMed

Insights

Chicken anemia virus (CAV) protein Apoptin kills cancer cells by entering the nucleus. Human Peptidyl-prolyl isomerase-like 3 (Ppil3) binds Apoptin, retaining it in the cytoplasm and inhibiting cell death.

Area of Science:

  • Oncology
  • Virology
  • Molecular Biology

Background:

  • Apoptin, a protein from chicken anemia virus (CAV), selectively induces apoptosis in cancer cells.
  • Apoptin's cell-killing function is dependent on its nuclear localization, which occurs specifically in cancer cells.
  • The precise mechanisms regulating Apoptin's nucleocytoplasmic shuttling remain incompletely understood.

Purpose of the Study:

  • To identify proteins interacting with Apoptin and investigate their role in regulating its cellular localization.
  • To elucidate the function of Peptidyl-prolyl isomerase-like 3 (Ppil3) in Apoptin-mediated cell death.
  • To explore the potential of targeting the Apoptin-Ppil3 interaction for cancer therapy.

Main Methods:

  • Yeast two-hybrid screening to identify Apoptin-interacting proteins.
  • Co-immunoprecipitation and Western blotting to confirm direct binding between Apoptin and Ppil3.
  • Cellular localization studies using immunofluorescence microscopy in normal and cancer cell lines.
  • Manipulation of Ppil3 expression levels (overexpression and knockdown) to assess its impact on Apoptin localization.
  • Site-directed mutagenesis of Apoptin to investigate the role of specific residues in Ppil3 interaction.

Main Results:

  • Human Peptidyl-prolyl isomerase-like 3 (Ppil3) was identified as a direct binding partner of Apoptin.
  • Ppil3 binds Apoptin and retains it in the cytoplasm, even in cancer cells.
  • The nucleocytoplasmic distribution of Apoptin is directly correlated with the endogenous expression level of Ppil3.
  • Modulating Ppil3 levels exogenously alters Apoptin's localization.
  • An Apoptin mutant (P109A) located near putative nuclear signals significantly impaired Ppil3's inhibitory function.

Conclusions:

  • Ppil3 acts as a cytoplasmic anchor for Apoptin, inhibiting its nuclear translocation and subsequent cell death induction.
  • The interaction between Apoptin and Ppil3 represents a critical regulatory step in Apoptin's tumor-specific activity.
  • These findings offer new insights into Apoptin's localization mechanism and suggest Ppil3 as a potential therapeutic target in cancer treatment.

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