Ca2+-dependent expression of the CIRCE regulon in Streptococcus pneumoniae.

DnaK and GroEL play a pivotal role in protein folding, and promote cell proliferation and survival. In Gram-positive and several Gram-negative bacteria, HrcA represses the transcription of dnaK and groE operons by binding to the highly conserved CIRCE (controlling inverted repeat of chaperone expression) operator sequence in the presence of GroEL. HrcA may respond to environmental stress and various other factors that modulate the transcription of the dnaK and groE operons. However, the mechanisms by which these factors modulate the activity of HrcA remain elusive. Here, we show that the thermoresistance of Streptococcus pneumoniae is significantly repressed in the presence of Ca2+. Furthermore, heat shock-induced expression of the CIRCE regulon in S. pneumoniae is repressed in the presence of Ca2+, although to a lesser degree than in the hrcA mutant, strongly suggesting that HrcA inhibits expression of the CIRCE regulon in a Ca2+-dependent manner. Although HrcA does not bind directly to Ca2+, its hydrophobicity is increased in the presence of the metal ion. Taken together, our observations suggest that Ca2+ induces conformational changes, such as exposure of the hydrophobic surfaces of HrcA, which facilitate binding to GroEL. Alternatively, the presence of Ca2+ may facilitate GroEL in interacting freely with HrcA. This, in turn, enhances access to CIRCE and leads to repression of the dnaK and groE operons in S. pneumoniae.