Thermal and Nutritional Regulation of Ribosome Hibernation in Staphylococcus aureus

• Published in: Journal of bacteriology 2018-12, Vol.200 (24)
• Main Authors: Basu, Arnab, Shields, Kathryn E, Eickhoff, Christopher S, Hoft, Daniel F, Yap, M N
• Format: Article
• Language: English
• Subjects: Amino acids; Antibiotics; Bacterial proteins; Bacteriology; Biofilms; Cyanobacteria; Darkness; Derepression; Dimerization; Drug resistance; Epistasis; Firmicutes; Guanosine triphosphate; Hibernation; Homeostasis; Infectivity; Masks; Metabolism; Nutrients; Nutrition; Opportunist infection; Pathogens; Proteins; Regulators; Ribosomes; Sigma factor; Stability; Staphylococcus aureus; Staphylococcus infections; Stationary phase; Stress; Stresses; Temperature dependence; Translation; Virulence
• ISSN: 0021-9193; 1098-5530
• DOI: 10.1128/JB.00426-18

The translationally silent 100S ribosome is a poorly understood form of the dimeric 70S complex that is ubiquitously found in all bacterial phyla. The elimination of the hibernating 100S ribosome leads to translational derepression, ribosome instability, antibiotic sensitivity, and biofilm defects in some bacteria. In , such as the opportunistic pathogen , a 190-amino acid protein called ibernating- romoting actor (HPF) dimerizes and conjoins two 70S ribosomes through a direct interaction between the HPF homodimer, with each HPF monomer tethered on an individual 70S complex. While the formation of the 100S ribosome in gammaproteobacteria and cyanobacteria is exclusively induced during postexponential growth phase and darkness, respectively, the 100S ribosomes in are constitutively produced from the lag-logarithmic phase through the post-stationary phase. Very little is known about the regulatory pathways that control expression and 100S ribosome abundance. Here, we show that a general stress response (GSR) sigma factor (SigB) and a GTP-sensing transcription factor (CodY) integrate nutrient and thermal signals to regulate synthesis in , resulting in an enhanced virulence of the pathogen in a mouse model of septicemic infection. CodY-dependent regulation of is strain specific. An epistasis analysis further demonstrated that CodY functions upstream of the GSR pathway in a condition-dependent manner. The results reveal an important link between stress physiology, ribosome metabolism, and infection biology. The dimerization of 70S ribosomes (100S complex) plays an important role in translational regulation and infectivity of the major human pathogen Although the dimerizing factor HPF has been characterized biochemically, the pathways that regulate 100S ribosome abundance remain elusive. We identified a metabolite- and nutrient-sensing transcription factor, CodY, that serves both as an activator and a repressor of expression in nutrient- and temperature-dependent manners. Furthermore, CodY-mediated activation of masks a secondary transcript derived from a general stress response SigB promoter. CodY and SigB regulate a repertoire of virulence genes. The unexpected link between ribosome homeostasis and the two master virulence regulators provides new opportunities for alternative druggable sites.