ClpL is required for folding of CtsR in Streptococcus mutans.

ClpL, a member of the HSP100 family, is widely distributed in Gram-positive bacteria but is absent in Gram-negative bacteria. Although ClpL is involved in various cellular processes, such as the stress tolerance response, long-term survival, virulence, and antibiotic resistance, the detailed molecular mechanisms are largely unclear. Here we report that ClpL acts as a chaperone to properly fold CtsR, a stress response repressor, and prevents it from forming protein aggregates in Streptococcus mutans. In vitro, ClpL was able to successfully refold urea-denatured CtsR but not aggregated proteins. We suggest that ClpL recognizes primarily soluble but denatured substrates and prevents the formation of large protein aggregates. We also found that in vivo, the C-terminal D2-small domain of ClpL is essential for the observed chaperone activity. Since ClpL widely contributes to various cellular functions, we speculate that ClpL chaperone activity is necessary to maintain cellular homeostasis.