title: Stressed mycobacteria use the chaperone ClpB to sequester irreversibly oxidized proteins asymmetrically within and between cells.
abstract: Mycobacterium tuberculosis (Mtb) defends itself against host immunity and chemotherapy at several levels, including the repair or degradation of irreversibly oxidized proteins (IOPs). To investigate how Mtb deals with IOPs that can neither be repaired nor degraded, we used new chemical and biochemical probes and improved image analysis algorithms for time-lapse microscopy to reveal a defense against stationary phase stress, oxidants, and antibiotics--the sequestration of IOPs into aggregates in association with the chaperone ClpB, followed by the asymmetric distribution of aggregates within bacteria and between their progeny. Progeny born with minimal IOPs grew faster and better survived a subsequent antibiotic stress than their IOP-burdened sibs. ClpB-deficient Mtb had a marked recovery defect from stationary phase or antibiotic exposure and survived poorly in mice. Treatment of tuberculosis might be assisted by drugs that cripple the pathway by which Mtb buffers, sequesters, and asymmetrically distributes IOPs.
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Vaubourgeix
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Lin
authors.affiliation: School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), SV 3834, Station 19, CH-1015 Lausanne, Switzerland.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Dhar
authors.affiliation: Department of Physiology and Neuroscience, New York University, Langone Medical Center, New York, NY 10016, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chenouard
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Xiuju
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Helene
authors.initials: H
authors.lastname: Botella
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Tania
authors.initials: T
authors.lastname: Lupoli
authors.affiliation: School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), SV 3834, Station 19, CH-1015 Lausanne, Switzerland; Biomedical Imaging Group, Swiss Federal Institute of Technology in Lausanne (EPFL), BM 4.134, Station 17, CH-1015 Lausanne, Switzerland.
authors.forename: Olivia
authors.initials: O
authors.lastname: Mariani
authors.affiliation: Organic Synthesis Core Facility, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Guangli
authors.initials: G
authors.lastname: Yang
authors.affiliation: Organic Synthesis Core Facility, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ouathek
authors.initials: O
authors.lastname: Ouerfelli
authors.affiliation: Biomedical Imaging Group, Swiss Federal Institute of Technology in Lausanne (EPFL), BM 4.134, Station 17, CH-1015 Lausanne, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Unser
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schnappinger
authors.affiliation: School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), SV 3834, Station 19, CH-1015 Lausanne, Switzerland.
authors.forename: John
authors.initials: J
authors.lastname: McKinney
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: cnathan@med.cornell.edu.
authors.forename: Carl
authors.initials: C
authors.lastname: Nathan
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D001426:Bacterial Proteins / Q000378:metabolism*; D049071:Endopeptidase Clp / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D050296:Microbial Viability / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development / Q000502:physiology; D016877:Oxidants / Q000633:toxicity; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D066329:Protein Aggregates; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D021381:Protein Transport
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D016877:Oxidants; D066329:Protein Aggregates; D049071:Endopeptidase Clp