title: Mycobacterium tuberculosis septum site determining protein, Ssd encoded by rv3660c, promotes filamentation and elicits an alternative metabolic and dormancy stress response.
abstract: BACKGROUND
  Proteins that are involved in regulation of cell division and cell cycle progression remain undefined in Mycobacterium tuberculosis. In addition, there is a growing appreciation that regulation of cell replication at the point of division is important in establishing a non-replicating persistent state. Accordingly, the objective of this study was to use a systematic approach consisting of consensus-modeling bioinformatics, ultrastructural analysis, and transcriptional mapping to identify septum regulatory proteins that participate in adaptive metabolic responses in M. tuberculosis.
  
  
  RESULTS
  Septum site determining protein (Ssd), encoded by rv3660c was discovered to be an ortholog of septum site regulating proteins in actinobacteria by bioinformatics analysis. Increased expression of ssd in M. smegmatis and M. tuberculosis inhibited septum formation resulting in elongated cells devoid of septa. Transcriptional mapping in M. tuberculosis showed that increased ssd expression elicited a unique response including the dormancy regulon and alternative sigma factors that are thought to play a role in adaptive metabolism. Disruption of rv3660c by transposon insertion negated the unique transcriptional response and led to a reduced bacterial length.
  
  
  CONCLUSIONS
  This study establishes the first connection between a septum regulatory protein and induction of alternative metabolism consisting of alternative sigma factors and the dormancy regulon that is associated with establishing a non-replicating persistent intracellular lifestyle. The identification of a regulatory component involved in cell cycle regulation linked to the dormancy response, whether directly or indirectly, provides a foundation for additional studies and furthers our understanding of the complex mechanisms involved in establishing a non-replicating state and resumption of growth.
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: England
authors.forename: Rebecca
authors.initials: R
authors.lastname: Crew
authors.forename: Richard A
authors.initials: RA
authors.lastname: Slayden
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D019295:Computational Biology; D004251:DNA Transposable Elements; D015870:Gene Expression; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D055786:Gene Knockout Techniques; D006801:Humans; D008855:Microscopy, Electron, Scanning; D016254:Mutagenesis, Insertional; D020102:Mycobacterium smegmatis / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D018085:Regulon; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D012808:Sigma Factor / Q000096:biosynthesis; D013312:Stress, Physiological
chemical_list: D001426:Bacterial Proteins; D004251:DNA Transposable Elements; D012808:Sigma Factor