Molecular mechanism and functional role of brefeldin A-mediated ADP-ribosylation of CtBP1/BARS

Antonino Colanzi, Giovanna Grimaldi, Giuliana Catara, Carmen Valente, Claudia Cericola, Prisca Liberali, Maurizio Ronci, Vasiliki S. Lalioti, Agostino Bruno, Andrea R. Beccari, Andrea Urbani, Antonio De Florah, Marco Nardini, Martino Bolognesi, Alberto Luini, Daniela Corda

Research output: Contribution to journalArticlepeer-review

Abstract

ADP-ribosylation is a posttranslational modification that modulates the functions of many target proteins. We previously showed that the fungal toxin brefeldin A (BFA) induces the ADP-ribosylation of C-terminal-binding protein-1 short-form/BFA-ADP-ribosylation substrate (CtBP1-S/BARS), a bifunctional protein with roles in the nucleus as a transcription factor and in the cytosol as a regulator of membrane fission during intracellular trafficking and mitotic partitioning of the Golgi complex. Here, we report that ADP-ribosylation of CtBP1-S/BARS by BFA occurs via a nonconventional mechanism that comprises two steps: (i) synthesis of a BFA-ADP-ribose conjugate by the ADP-ribosyl cyclase CD38 and (ii) covalent binding of the BFA-ADP-ribose conjugate into the CtBP1-S/BARS NAD+-binding pocket. This results in the locking of CtBP1-S/BARS in a dimeric conformation, which prevents its binding to interactors known to be involved in membrane fission and, hence, in the inhibition of the fission machinery involved in mitotic Golgi partitioning. As this inhibition may lead to arrest of the cell cycle in G2, these findings provide a strategy for the design of pharmacological blockers of cell cycle in tumor cells that express high levels of CD38.

Original languageEnglish
Pages (from-to)9794-9799
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number24
DOIs
Publication statusPublished - Jun 11 2013

Keywords

  • Anticancer molecules
  • Cell signaling
  • Golgi fragmentation
  • Mitosis

ASJC Scopus subject areas

  • General

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