title: Molecular mechanism and functional role of brefeldin A-mediated ADP-ribosylation of CtBP1/BARS.
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.
authors.affiliation: Institute of Protein Biochemistry, National Research Council, 80131 Naples, Italy. a.colanzi@ibp.cnr.it
authors.forename: Antonino
authors.initials: A
authors.lastname: Colanzi
authors.forename: Giovanna
authors.initials: G
authors.lastname: Grimaldi
authors.forename: Giuliana
authors.initials: G
authors.lastname: Catara
authors.forename: Carmen
authors.initials: C
authors.lastname: Valente
authors.forename: Claudia
authors.initials: C
authors.lastname: Cericola
authors.forename: Prisca
authors.initials: P
authors.lastname: Liberali
authors.forename: Maurizio
authors.initials: M
authors.lastname: Ronci
authors.forename: Vasiliki S
authors.initials: VS
authors.lastname: Lalioti
authors.forename: Agostino
authors.initials: A
authors.lastname: Bruno
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Beccari
authors.forename: Andrea
authors.initials: A
authors.lastname: Urbani
authors.forename: Antonio
authors.initials: A
authors.lastname: De Flora
authors.forename: Marco
authors.initials: M
authors.lastname: Nardini
authors.forename: Martino
authors.initials: M
authors.lastname: Bolognesi
authors.forename: Alberto
authors.initials: A
authors.lastname: Luini
authors.forename: Daniela
authors.initials: D
authors.lastname: Corda
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000378:metabolism; D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D000429:Alcohol Oxidoreductases / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D015153:Blotting, Western; D020126:Brefeldin A / Q000378:metabolism* / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D008958:Models, Molecular; D009243:NAD / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017434:Protein Structure, Tertiary; D051381:Rats
chemical_list: D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D009243:NAD; D020126:Brefeldin A; D000246:Adenosine Diphosphate Ribose; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1
keywords: Golgi fragmentation; anticancer molecules; cell signaling; mitosis