Toward Novel Therapeutics for TSC and LAM: Using Mechanisms of a Bacterial Protein to Sensitize Cells to Rapamycin
Abstract
This project is based on our discovery that a bacterial protein (Shigella OspB) sensitizes mammalian cells to rapamycin-mediated inhibition of mTORC1 and that this mechanism of sensitizing cells to rapamycin appears to be conserved across divergent branches of life. The most significant finding of the current funding period is that the arginine N-end rule pathway and the inositol phosphate hexakisphosphate are required for OspB function. We isolated or generated anew, and confirmed, Saccharomyces cerevisiae strains with deletions in each of the genes that encode the first three steps of the arginine N-end rule pathway (nta1, ate1, and rad6), in the gene that encodes the enzyme that synthesizes hexakisphosphate (ipk1), and in genes that encode the enzyme that convert hexakisphosphate to pyrophosphate molecules (vip1 and ksc1). We found that each of the genes that encode the first three steps of the arginine N-end rule pathway and ipk1 are required for OspB function, but that vip1 and ksc1 are not. In follow-up to these results, we will test the role of these pathways in the function of OspB in mammalian cells. These findings provide new insight into OspB function.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2018
- Accession Number
- AD1063028
Entities
People
- Marcia B Goldberg
Organizations
- Massachusetts General Hospital