Absolutely conserved, highly abundant, and present in all cells and organisms studied, polyphosphates (polyPs) are one of the most ancient macromolecules found on earth. They consist of long chains of phosphates, linked by high-energy phosphoanhydride bonds. PolyP has been shown to play crucial roles in bacterial pathogenesis, biofilm formation, stress resistance and blood clotting, and has been implicated in signaling processes and cancer. Despite these important functions, however, little is known about the mechanism(s) by which polyP influences these diverse processes. Based on our most recent discoveries we now postulate that polyP affects this wide and seemingly unrelated range of biological functions by using a single, unifying mechanism: serving as a scaffold that stabilizes protein folding intermediates. This would explain how polyP confers resistance to stress conditions that cause protein unfolding and accelerates processes, such as biofilm formation, which involve the stabilization of amyloid-like proteins in a fiber-forming conformation We propose to investigate the precise mechanism by which polyP influences these processes using a combination of genetic, biochemical, and structural approaches. We will exploit the facts that polyP- deficient bacteria are exquisitely sensitive towards the physiological antimicrobial HOCl (i.e., bleach) and impaired in biofilm formation to develop novel antimicrobials. We will investigate the role of polyP as member of the eukaryotic proteostasis network and expand on our discovery that polyP accelerates disease-related amyloid fiber formation, the leading cause of protein folding diseases, such as Alzheimer's Disease. These studies will reveal polyP's physiological role in eukaryotic organisms, significantly expanding the knowledge about this prebiotic molecule. The results will aid in the development of more effective antimicrobials and strategies to modulate the onset of age-related pathologies.

Public Health Relevance

Polyphosphates, which are highly abundant and universally conserved polymers that are present in every cell and organism studied, date all the way back to prebiotic times. We recently discovered that polyphosphates function as highly effective protein-stabilizing biomolecules, protecting bacteria against stress conditions and modulating the formation of amyloid-like fibers, the leading cause of protein folding diseases, such as Alzheimer's Disease. We will now capitalize on these findings with the goal to develop more effective antimicrobials and devise novel strategies that delay the onset of these age-related pathologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM116582-02
Application #
9118242
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Maas, Stefan
Project Start
2015-08-01
Project End
2019-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Voth, Wilhelm; Jakob, Ursula (2017) Stress-Activated Chaperones: A First Line of Defense. Trends Biochem Sci 42:899-913
Dahl, Jan-Ulrik; Gray, Michael J; Bazopoulou, Daphne et al. (2017) The anti-inflammatory drug mesalamine targets bacterial polyphosphate accumulation. Nat Microbiol 2:16267
Groitl, Bastian; Dahl, Jan-Ulrik; Schroeder, Jeremy W et al. (2017) Pseudomonas aeruginosa defense systems against microbicidal oxidants. Mol Microbiol 106:335-350
Docter, Brianne E; Horowitz, Scott; Gray, Michael J et al. (2016) Do nucleic acids moonlight as molecular chaperones? Nucleic Acids Res 44:4835-45
Cremers, Claudia M; Knoefler, Daniela; Gates, Stephanie et al. (2016) Polyphosphate: A Conserved Modifier of Amyloidogenic Processes. Mol Cell 63:768-80