Postdoctoral fellowship

DESCRIPTION

The TOR (Target of Rapamycin) pathwayis a conserved signaling pathway in all eukaryotes that integrates various nutritional and hormonal signals to regulate cell growth. Rapamycin, a molecule isolated from extracts of Streptomyces hygroscopicus, forms a complex with FKBP12 and TOR proteins in this pathway (Choi et al., 1996). This complex inhibits the kinase activity of the TOR protein, leading to a halt in cell growth. Initially isolated for its antifungal activity, rapamycin is currently used in various treatments, including anti-inflammatory, anti-rejection (transplant), and anti-cancer therapies. However, other molecules, such as FK506 and FK520, produced by Streptomyces species, target the FKBP12 protein independently of TOR (Riveira and Heitman, 2023), suggesting that other molecules can affect cell growth through mechanisms different from that of rapamycin. 

Preliminary confrontation experiments between Streptomyces strains from different phylogenetic clades (which do not produce rapamycin) and the fungus Phanerochaete chrysosporium showed fungal growth inhibition in 13 out of 14 cases (Bontemps et al., 2013). This result suggests that the full diversity of molecules produced by Streptomyces has yet to be explored for their antifungal potential. P. chrysosporium is a wood-decaying fungus; its specific ecological niche provides nutrient resources rich in sugars and low in nitrogen, making it an ideal organism to study the TOR signaling pathway (Noel et al., 2021). In this fungus, the various components of the TOR pathway are conserved (Nguyen et al., 2020) and a collection of mutants, produced by UV and selected for their resistance to Rapamycin is available in the Lab.

The postdoctoral research will aim at identifying new molecules produced by Streptomyces thanks to their antifungal activity against P. chrysosporium. First, confrontation experiments between strains of Streptomyces and P. chrysosporium will be carried out in order to determine the antifungal effects of those strains. The same confrontation experiments will be carried out between the identified strains and the mutants resistant to rapamycin in order to classify the molecules produced according to their mechanism of action (linked or not to TOR or FKBP12). These experiments should make it possible to quickly classify the molecules that will have to be isolated and characterized in more detail. The genomes of the Streptomyces strains producing the molecules of interest can then be analyzed in order to identify the biosynthesis genes of these molecules, and the generation of deletion mutants will make it possible to validate their function.

Bontemps, C., Toussaint, M., Revol, P.-V., Hotel, L., Jeanbille, M., Uroz, S., Turpault, M.-P., Blaudez, D., Leblond, P., 2013. Taxonomic and functional diversity of Streptomyces in a forest soil. FEMS Microbiol. Lett. 342, 157–167. https://doi.org/10.1111/1574-6968.12126

Choi, J., Chen, J., Schreiber, S.L., Clardy, J., 1996. Structure of the FKBP12-Rapamycin Complex Interacting with Binding Domain of Human FRAP. Science 273, 239–242. https://doi.org/10.1126/science.273.5272.239

Nguyen, D.V., Roret, T., Fernandez-Gonzalez, A., Kohler, A., Morel-Rouhier, M., Gelhaye, E., Sormani, R., 2020. Target Of Rapamycin pathway in the white-rot fungus Phanerochaete chrysosporium. PloS One 15, e0224776. https://doi.org/10.1371/journal.pone.0224776

Nicault, M., Zaiter, A., Dumarcay, S., Chaimbault, P., Gelhaye, E., Leblond, P., Bontemps, C., 2021. Elicitation of antimicrobial active compounds by Streptomyces-fungus co-cultures. Microorganisms 9, 178.

Noel, D., 2023. Caractérisation de mutants de Phanerochaete chrysosporium Résistants à des Extractibles de bois (CAREX). theses.fr. Université de Lorraine.

Noël, D., Nguyen, D.V., Sormani, R., 2021. How to rot: A role for TOR. Interplay between carbon catabolite repression and TOR signaling pathway. Adv. Bot. Res. 99, 151–173.

Rivera, A., Heitman, J., 2023. Natural product ligands of FKBP12: Immunosuppressive antifungal agents FK506, rapamycin, and beyond. PLOS Pathog. 19, e1011056. https://doi.org/10.1371/journal.ppat.1011056

SELECTION CRITERIA

The applicant should have:

• A PhD in microbiology or a related field.
• Proven skills in bacterial biology, filamentous fungi biology, and molecular biology.

TERMS AND TENURE
This one-year position will be based at the UMR 1136 IAM team stress response and redox regulation (Nancy, FST campus aiguillette)  The duration cannot exceed 24 months.

The target start date for the position is 6/01/25, with some flexibility on the exact start date.

HOW TO APPLY 
Applicants are requested to submit the following materials:
• A cover letter applying for the position
• Full CV and list of publications
• Academic transcripts (unofficial versions are fine)

Deadline for application is 27/11/24. Applicants will be interviewed by an Ad Hoc Commission by 29/11/24.

Applications are only accepted through email. All document must be sent to rodnay.sormani@univ-lorraine.fr 

JOB LOCATION

Nancy, Lorraine, France

REQUIREMENTS

DOCUMENTS

• Curriculum Vitae - Your most recently updated C.V. including list of publications
• Cover Letter
• Statement of Research