UNRAVELING THE CELLULAR SULFENOME: A SEARCH FOR NEW REDOX-REGULATED PATHWAYS
Within proteins, cysteine residues are sensitive to oxidation by reactive oxygen species (ROS). The first oxidation product of cysteines exposed to ROS is the sulfenic acid derivative (-SOH).
Sulfenic acids are highly reactive intermediates that, unless they are stabilized within the protein microenvironment, react with another cysteine present in the vicinity to form a disulfide or are further oxidized to the irreversible sulfinic (-SO2H) and sulfonic (-SO3H) acid modifications.
Sulfenic acid formation has traditionally been viewed as an unwanted reaction opening the way to damages that are harmful to proteins.
However, it has become clear in recent years that formation of sulfenic acids is not always deleterious to the cell.
A new concept is emerging, in which sulfenylation of specific cysteine residues modulates signal transduction pathways by altering the activity and function of cellular proteins, just as phosphorylation and dephosphorylation cycles regulate enzyme activities and cellular pathways. However, the modulation of protein function by sulfenic acid formation has been unambiguously shown for only a few proteins.
We postulate that specific oxidation of cysteine residues via sulfenylation modulates the activity of many more proteins and pathways and that numerous sulfenylation sites have not yet been recognized.
We want to apply an unprecedented multi-facetted approach to fully grasp the physiological scope of cysteine sulfenic acid formation by uncovering the sulfenome of a living organism, using Escherichia coli as a model.
The main objectives of our research program are :
- to comprehensively characterize the sulfenome of E. coli,
- to identify new proteins and pathways regulated by sulfenylation and
- to understand how sulfenylation is controlled at the cellular level.
If our hypothesis proves to be true, our project will uncover a new “redox dimension” affecting many cellular processes and pathways, opening up new avenues of investigation.
This project has received funding from the European Research Council (ERC) under the European Union's Seventh Framework Programme under the grant agreement number 282335.