1. Academic Validation
  2. Molecular mechanism and functional role of brefeldin A-mediated ADP-ribosylation of CtBP1/BARS

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

  • Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9794-9. doi: 10.1073/pnas.1222413110.
Antonino Colanzi 1 Giovanna Grimaldi Giuliana Catara Carmen Valente Claudia Cericola Prisca Liberali Maurizio Ronci Vasiliki S Lalioti Agostino Bruno Andrea R Beccari Andrea Urbani Antonio De Flora Marco Nardini Martino Bolognesi Alberto Luini Daniela Corda
Affiliations

Affiliation

  • 1 Institute of Protein Biochemistry, National Research Council, 80131 Naples, Italy. [email protected]
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.

Keywords

Golgi fragmentation; anticancer molecules; cell signaling; mitosis.

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