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.
Highlights
Our understanding of how bacteria regulate cellular processes has long focused on the role of transcription factors in the modulation of cellular responses
While this suggested an active role of proteolysis in the regulation of bacterial physiology, it has been difficult to determine the functional significance of protein degradation by these proteolytic machines in bacteria
Clp protease is essential in Mycobacterium tuberculosis The essentiality of Clp protease has been demonstrated in the non-pathogenic, fast growing model organism, Mycobacterium smegmatis (Msm), but not in Mycobacterium tuberculosis (Mtb)
Summary
Our understanding of how bacteria regulate cellular processes has long focused on the role of transcription factors in the modulation of cellular responses. Bacteria possess an array of compartmentalized proteolytic complexes, capable of degrading proteins into smaller polypeptides and amino acids[3,4]. They were thought to maintain protein quality control through the recognition of misfolded, aberrant protein products. Several studies identified an array of endogenous proteins that were targeted for degradation in bacteria[5,6] While this suggested an active role of proteolysis in the regulation of bacterial physiology, it has been difficult to determine the functional significance of protein degradation by these proteolytic machines in bacteria
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