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Mycobacterium tuberculosis ClpP1 and ClpP2 function together in protein degradation and are required for viability in vitro and during infection
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Ehrt, Sabine, Raju, Ravikiran M., Unnikrishnan, Meera, Rubin, Daniel H. F., Krishnamoorthy, Vidhya, Kandror, Olga, Akopian, Tatos N., Goldberg, Alfred L. and Rubin, Eric J. (2012) Mycobacterium tuberculosis ClpP1 and ClpP2 function together in protein degradation and are required for viability in vitro and during infection. PLoS Pathogens, Volume 8 (Number 2). Article number e1002511. doi:10.1371/journal.ppat.1002511 ISSN 1553-7374.
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Official URL: http://dx.doi.org/10.1371/journal.ppat.1002511
Abstract
In most bacteria, Clp protease is a conserved, non-essential serine protease that regulates the response to various stresses. Mycobacteria, including Mycobacterium tuberculosis (Mtb) and Mycobacterium smegmatis, unlike most well studied prokaryotes, encode two ClpP homologs, ClpP1 and ClpP2, in a single operon. Here we demonstrate that the two proteins form a mixed complex (ClpP1P2) in mycobacteria. Using two different approaches, promoter replacement, and a novel system of inducible protein degradation, leading to inducible expression of clpP1 and clpP2, we demonstrate that both genes are essential for growth and that a marked depletion of either one results in rapid bacterial death. ClpP1P2 protease appears important in degrading missense and prematurely terminated peptides, as partial depletion of ClpP2 reduced growth specifically in the presence of antibiotics that increase errors in translation. We further show that the ClpP1P2 protease is required for the degradation of proteins tagged with the SsrA motif, a tag co-translationally added to incomplete protein products. Using active site mutants of ClpP1 and ClpP2, we show that the activity of each subunit is required for proteolysis, for normal growth of Mtb in vitro and during infection of mice. These observations suggest that the Clp protease plays an unusual and essential role in Mtb and may serve as an ideal target for antimycobacterial therapy.
Item Type: | Journal Article | ||||
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Subjects: | Q Science > QP Physiology Q Science > QR Microbiology |
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Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Microbiology & Infection Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Library of Congress Subject Headings (LCSH): | Mycobacterium tuberculosis, Proteins, Proteolytic enzymes | ||||
Journal or Publication Title: | PLoS Pathogens | ||||
Publisher: | Public Library of Science | ||||
ISSN: | 1553-7374 | ||||
Official Date: | February 2012 | ||||
Dates: |
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Volume: | Volume 8 | ||||
Number: | Number 2 | ||||
Article Number: | Article number e1002511 | ||||
DOI: | 10.1371/journal.ppat.1002511 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access | ||||
Funder: | National Institute of Allergy and Infectious Diseases (U.S.) (NIAID), National Institute of General Medical Sciences (U.S.) (NIGMS), Harvard Catalyst, Bill & Melinda Gates Foundation | ||||
Grant number: | R01 AI071881 (NIAD), R01 GM51923 (NIGMS) |
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