title: Mycobacterium tuberculosisprotease MarP activates a peptidoglycan hydrolase during acid stress.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Helene
authors.initials: H
authors.lastname: Botella
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Vaubourgeix
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Myung Hee
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Song
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Weizhen
authors.initials: W
authors.lastname: Xu
authors.affiliation: Division of Infectious Diseases, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Hideki
authors.initials: H
authors.lastname: Makinoshima
authors.affiliation: Division of Infectious Diseases, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Glickman
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA sae2004@med.cornell.edu.
authors.forename: Sabine
authors.identifier: 0000-0002-7951-2310
authors.initials: S
authors.lastname: Ehrt
mesh_terms: D000143:Acids / Q000633:toxicity*; D001426:Bacterial Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D015964:Gene Expression Regulation, Bacterial; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000235:genetics / Q000502:physiology*; D009238:N-Acetylmuramoyl-L-alanine Amidase / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000172:deficiency / Q000378:metabolism*; D013312:Stress, Physiological
chemical_list: D000143:Acids; D001426:Bacterial Proteins; D010447:Peptide Hydrolases; D009238:N-Acetylmuramoyl-L-alanine Amidase
keywords: acid resistance; mycobacteria; peptidoglycan; protease