title: Post-translational regulation via Clp protease is critical for survival of Mycobacterium tuberculosis.
abstract: Unlike most bacterial species, Mycobacterium tuberculosis depends on the Clp proteolysis system for survival even in in vitro conditions. We hypothesized that Clp is required for the physiologic turnover of mycobacterial proteins whose accumulation is deleterious to bacterial growth and survival. To identify cellular substrates, we employed quantitative proteomics and transcriptomics to identify the set of proteins that accumulated upon the loss of functional Clp protease. Among the set of potential Clp substrates uncovered, we were able to unambiguously identify WhiB1, an essential transcriptional repressor capable of auto-repression, as a substrate of the mycobacterial Clp protease. Dysregulation of WhiB1 turnover had a toxic effect that was not rescued by repression of whiB1 transcription. Thus, under normal growth conditions, Clp protease is the predominant regulatory check on the levels of potentially toxic cellular proteins. Our findings add to the growing evidence of how post-translational regulation plays a critical role in the regulation of bacterial physiology.
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Ravikiran M
authors.initials: RM
authors.lastname: Raju
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Jedrychowski
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Jun-Rong
authors.initials: JR
authors.lastname: Wei
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Jessica T
authors.initials: JT
authors.lastname: Pinkham
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Annie S
authors.initials: AS
authors.lastname: Park
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Kathryn
authors.initials: K
authors.lastname: O'Brien
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: German
authors.initials: G
authors.lastname: Rehren
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schnappinger
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Rubin
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism*; D049071:Endopeptidase Clp / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D059748:Proteolysis; D040901:Proteomics; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D014157:Transcription Factors; C574744:WhiB1 protein, Mycobacterium tuberculosis; D049071:Endopeptidase Clp