Ravi Kaul and Wanda M. Wenman

Department of Pediatrics, Section of Infectious Diseases, 403 Neurosciences Building, School of Medicine, 1515 Newton Court, University of California, Davis, CA 95616

Received 2/16/ 98 Accepted 2/20/98

8. PERSPECTIVE

The presence of eukaryotic-like histones in pathogenic bacteria is intriguing and represents a heitherto unknown mechanism(s) of gene regulation. While in P.aeruginosa eukaryotic-like histone is involved in positive regulation of aliginate biosynthesis, chlamydial eukaryotic-like histone Hc1 condenses DNA and down regulates transcriptional and translational processes. These newly discovered basic proteins with homologies to eukaryotic histones may play a significant regulatory role in microbial pathogenesis. We have briefly summarized the functional role of Hc1 in DNA binding and condensation, along with its role in transcriptional and translational processes. However, the question why Hc1 binds preferentially to some sequences over others remains to be addressed. Structure-function study of chlamydial Hc1 has identified its carboxyl terminus as a DNA binding domain leading to chromatin compaction (as its eukaryotic counterpart) while the amino terminus is involved in protein-protein interactions. These observations may explain the ability of Hc1 to form higher order complexes with DNA that fail to migrate through agarose gels. The conservation of amino acid residues at the amino terminal domain simply supports the importance of protein-protein interactions in these processes.

Failure to detect Hc1 during early stages of the chlamydial developmental cycle has led to the suggestion that Hc1 may be lost following internalization. Identification of a novel histone protease which cleaves both free Hc1 and that associated with DNA in vitro may allude to Hc1 loss during the early stages of chlamydial infection. However, localization and quantitation of the amount of Hc1 associated with EB and RB forms of the developmental cycle must be determined in order to understand the sequence of events leading to Hc1 undetectability. In addition, the question how histone protease gains access to condensed chromatin in vivo remains to be addressed. Efforts are underway in our laboratory to examine whether relaxation of chlamydial chromatin involves Hc1 phosphorylation and subsequent degradation. Eventually, an understanding of the process of DNA condensation and decondensation, which appears fundamental to chlamydial pathogenesis, may lead to novel therapeutic strategies.