Abstract
Bacterial cell growth and division require coordinated cell wall hydrolysis and synthesis, allowing for the removal and expansion of cell wall material. Without proper coordination, unchecked hydrolysis can result in cell lysis. How these opposing activities are simultaneously regulated is poorly understood. In Mycobacterium tuberculosis, the resuscitation-promoting factor B (RpfB), a lytic transglycosylase, interacts and synergizes with Rpf-interacting protein A (RipA), an endopeptidase, to hydrolyze peptidoglycan. However, it remains unclear what governs this synergy and how it is coordinated with cell wall synthesis. Here we identify the bifunctional peptidoglycan-synthesizing enzyme, penicillin binding protein 1 (PBP1), as a RipA-interacting protein. PBP1, like RipA, localizes both at the poles and septa of dividing cells. Depletion of the ponA1 gene, encoding PBP1 in M. smegmatis, results in a severe growth defect and abnormally shaped cells, indicating that PBP1 is necessary for viability and cell wall stability. Finally, PBP1 inhibits the synergistic hydrolysis of peptidoglycan by the RipA-RpfB complex in vitro. These data reveal a post-translational mechanism for regulating cell wall hydrolysis and synthesis through protein–protein interactions between enzymes with antagonistic functions.
Highlights
Mycobacterium tuberculosis, the causative agent of tuberculosis, kills approximately two million people each year and remains dormant within an estimated one-third of the world’s population [1]
Bacteria must tightly coordinate the processes of cell wall hydrolysis and synthesis
We previously demonstrated the interaction between two cell wall hydrolytic proteins, resuscitationpromoting factor B (RpfB) and Rpf-interacting protein A (RipA), in mycobacteria
Summary
Mycobacterium tuberculosis, the causative agent of tuberculosis, kills approximately two million people each year and remains dormant within an estimated one-third of the world’s population [1]. Reactivation likely relies upon the ability of mycobacteria to regulate the expansion and remodeling of cell wall material, an essential yet poorly understood bacterial process. Because cell wall biology is a rich area for antibiotic development, elucidating the mechanisms of essential cell wall processes in mycobacteria offers new avenues for chemotherapy targeted to actively growing or reactivating bacteria. Mycobacteria possess basic cell wall remodeling requirements similar to other bacteria, such that understanding mycobacterial cell wall homeostasis may provide new insights into universal paradigms of cell wall regulation. One such highly conserved area of cell wall remodeling is the need for regulation of peptidoglycan synthesis and degradation. Escherichia coli PG is composed of polysaccharides containing repeating disaccharide subunits of N-acetyl glucosamine and Nacetyl muramic acid, while mycobacterial PG contains N-acetyl glucosamine and a mixture of N-glycolyl muramic acid and N-
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