TY - JOUR
T1 - Molecular mechanism and functional role of brefeldin A-mediated ADP-ribosylation of CtBP1/BARS
AU - Colanzi, Antonino
AU - Grimaldi, Giovanna
AU - Catara, Giuliana
AU - Valente, Carmen
AU - Cericola, Claudia
AU - Liberali, Prisca
AU - Ronci, Maurizio
AU - Lalioti, Vasiliki S.
AU - Bruno, Agostino
AU - Beccari, Andrea R.
AU - Urbani, Andrea
AU - De Florah, Antonio
AU - Nardini, Marco
AU - Bolognesi, Martino
AU - Luini, Alberto
AU - Corda, Daniela
PY - 2013/6/11
Y1 - 2013/6/11
N2 - 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.
AB - 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.
KW - Anticancer molecules
KW - Cell signaling
KW - Golgi fragmentation
KW - Mitosis
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UR - http://www.scopus.com/inward/citedby.url?scp=84878981905&partnerID=8YFLogxK
U2 - 10.1073/pnas.1222413110
DO - 10.1073/pnas.1222413110
M3 - Article
C2 - 23716697
AN - SCOPUS:84878981905
VL - 110
SP - 9794
EP - 9799
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 24
ER -