Is CdtB a nuclease or a phosphatase?

Lara-Tejero and Galán (1) reported deoxyribonuclease (DNase) I–like activity of cytolethal distending toxin B (CdtB), which causes arrest in the G2/M transition phase of the cell cycle (2). Even though the authors noted that CdtB is a poor nuclease in vitro, they proposed that CdtB-inflicted DNA damage could trigger the checkpoint system that prevents cell entry into mitosis. A relationship between CdtB and DNase I similar to that observed by Lara-Tejero and Galán has recently been documented (3, 4). In those studies, however, both proteins were also identified as members of a broad metalloenzyme superfamily that includes, in addition to nucleases, various phosphatases of lipid second messengers such as sphingomyelin and inositol polyphosphate 5-phospate. In general, then, any protein of uncertain function belonging to this superfamily might be either a nuclease or a phosphatase. The exclusively nuclear localization of CdtB observed by Lara-Tejero and Galán argues against its phosphatase activity on lipid second messengers. A more likely group of CdtB targets are proteins that control tyrosine phosphorylation of the cell cycle regulator Cdc2 kinase, most notably the kinase Wee1 and the phosphatase Cdc25. These two proteins are regulated by distinct phosphatase/ kinase networks, but they have one thing in common: dephosphorylation of either leads to increased Cdc2 phosphorylation (5), which is a hallmark of cells treated by CdtB (2). Clearly, an unexplored possibility remains—that CdtB could be a phosphatase for either Wee1 kinase or Cdc25 phosphatase, or for other proteins in the upstream part of their regulatory networks (2). Finally, many unrelated proteins from pathogenic bacteria, most of which are of unknown function, have been identified as members of this nuclease/phosphatase superfamily (3). Elucidating molecular details of the CdtB-caused cell arrest could help generalize the mechanism or mechanisms of eukaryotic cell invasion by other pathogens as well.