Graduation Semester and Year
Spring 2024
Language
English
Document Type
Dissertation
Degree Name
Doctor of Philosophy in Quantitative Biology
Department
Biology
First Advisor
Cara C. Boutte
Second Advisor
Allan C. Clark
Third Advisor
Alison Ravenscraft
Fourth Advisor
Joseph Boll
Fifth Advisor
Shawn Christensen
Abstract
The disease Tuberculosis (TB) is caused by the pathogen Mycobacterium tuberculosis and was the cause of over one million deaths worldwide in 2023 (World Health Organization, 2023). TB treatment is difficult due to antibiotic tolerance and emerging resistance in Mtb strains. Mycobacterial cells have different regulatory mechanisms that allow them to adjust to myriad environmental stressors: these responses often lead to antibiotic tolerance. Therefore, studying responses to stress will lead to insights about antibiotic tolerance and treatment failure. Here, we specifically study two essential mycobacterial proteins, Wag31 and MmpL3, involved in cell wall metabolism. We show that Wag31 has distinct roles in the cell cycle, where it promotes polar elongation at the poles while inhibiting the initiation of elongation at the new pole, thus promoting asymmetric growth. Also, we find that Wag31 has a negative regulatory role in septation. Our data suggests that wag31 and mmpl3 are genetically linked and work together to regulate the elongation of the old pole. MmpL3 is a trehalose monomycolate transporter that is required for mycolic acid synthesis. We find that Wag31 and PlrA, another essential polar growth factor, recruit MmpL3 to the poles, and these three proteins may be required for the new pole to transition into the old pole. We also propose a novel role for the C-terminus of MmpL3 in regulating polar cell wall metabolism broadly in growth and stress, in promoting antibiotic resistance. In addition, we show that peptidoglycan and mycolic acid synthesis are tightly connected, which means that inhibition of MmpL3 reduces peptidoglycan metabolism and vice versa. Our work ultimately describes the molecular function of Wag31 and proposes a new model for cell wall metabolism in mycobacterial cells.
Keywords
Mycobacteria, Polar growth, elongation, deptation, Wag31, DivIVA, Mmpl3, peptidoglycan, Mycolic acid, trehalose mycolates
Disciplines
Bacteriology | Biochemistry | Cell Biology | Microbial Physiology | Molecular Biology | Structural Biology
License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Recommended Citation
Habibi Arejan, Neda, "A new model for polar growth in mycobacteria: the role of Wag31 and MmpL3 in cell wall synthesis" (2024). Biology Dissertations. 4.
https://mavmatrix.uta.edu/biology_dissertations/4
Included in
Bacteriology Commons, Biochemistry Commons, Cell Biology Commons, Microbial Physiology Commons, Molecular Biology Commons, Structural Biology Commons