cUMP, a novel second messenger – toxi-cUMPsignal

The functions of all cells in the human body are regulated by hormones and neurotransmitters (extracellular messengers) and transmitted within the cell by intracellular messengers. Intracellular messengers include the nucleotides cyclic-AMP (cAMP) and cyclic-GMP (cGMP). In many diseases, the balance of these messenger substances is disturbed, and accordingly many drugs act to restore the balance. The importance of cAMP and cGMP is also reflected in the fact that several Nobel Prizes have already been awarded in this field. In recent years, the non-canonical messengers cyclic-UMP (cUMP) and cyclic-CMP (cCMP) have been unambiguously identi?ed in many biological systems, including mammalian organs. However, the role of these signaling molecules in regulating the physiological functions of eukaryotic cells is still largely unknown. The fact that various dangerous bacterial toxins produce cUMP and cCMP suggests that they may play a role in infectious diseases. This hypothesis is supported by the fact that specialized enzymes that produce either cUMP or cCMP are widely distributed in bacteria. In bacteria, cCMP and cUMP play an important role in the defense against viral infections with bacteriophages.

In this context, we are bringing together a consortium of French and German scientists with strong complementary molecular expertise in this field to explore how cyclic UMP and CMP are produced and function in prokaryotic and eukaryotic cells. First, specific fluorescence sensors will be developed that will allow the precise tracking of these messenger substances in cells. This is also an important prerequisite for other researchers to be able to investigate the exact function of cUMP and cCMP in different body cells. In addition, we will identify protein targets and signaling pathways dependent on cUMP and cCMP in cells by using specific probes, transcriptome and phosphoproteome analyses. This is an important prerequisite for being able to influence these targets when they are dysregulated in diseases. Finally, we will study at the atomic scale the molecular mechanisms that regulate the catalytic activity of cUMP- or cCMP-generating enzymes in bacteria or eukaryotic cells and those that regulate the on/off signaling of their protein targets. This is also an important prerequisite for one day being able to influence these signaling pathways with drugs.

In summary, this Franco-German consortium has joined forces to launch a pioneering project in a new and hitherto poorly understood area of biology. Based on the knowledge on cAMP and cGMP, as well as research on bacterial toxins, we can assume that cUMP and cCMP are of great importance for normal functions of the human body and are dysregulated in important diseases. In the long term, the project will provide the basis for the development of new drugs for important diseases such as bacterial infections, some of which are no longer treatable with conventional drugs (antibiotics).