Mycobacterium tuberculosis (Mtb) can persist in the human host in a latent state for decades, in part because it has the ability to withstand numerous stresses imposed by host immunity. Prior studies have established the essentiality of the periplasmic protease MarP for Mtb to survive in acidified phagosomes and establish and maintain infection in mice. However, the proteolytic substrates of MarP that mediate these phenotypes were unknown. Here, we used biochemical methods coupled with supravital chemical probes that facilitate imaging of nascent peptidoglycan to demonstrate that during acid stress MarP cleaves the peptidoglycan hydrolase RipA, a process required for RipA's activation. Failure of RipA processing in MarP‐deficient cells leads to cell elongation and chain formation, a hallmark of progeny cell separation arrest. Our results suggest that sustaining peptidoglycan hydrolysis, a process required for cell elongation, separation of progeny cells, and cell wall homeostasis in growing cells, may also be essential for Mtb's survival in acidic conditions.
MarP is a periplasmic serine protease essential for Mycobacterium tuberculosis survival in acidic environments such as the phagolysosomal compartment. Identification of the peptidoglycan hydrolase RipA as MarP substrate suggests that RipA activation ensures the separation of progeny cells in acidic environments.
Mycobacterial cells that lack MarP elongate and form chains when subjected to acidic pH.
MarP cleaves the peptidoglycan hydrolase RipA in vitro to release its hydrolysis domain.
RipA and MarP interact in acid‐stressed cells, a condition where activation of RipA by MarP cleavage becomes essential to assure separation of progeny cells.
The EMBO Journal (2017) 36: 536–548
- Received June 15, 2016.
- Revision received November 28, 2016.
- Accepted December 2, 2016.
- © 2017 The Authors
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