Genetic complexity of the human hsp 60 gene

Hsp 60 is a chaperonin protein, homologous to GroEL of Escherichia coli and highly conserved across species. Immune response induced by the hsp 60 equivalent of numerous microorganisms elicits in animals and man a dominant cross-reactive T lymphocyte response. Hsp 60 has been strongly implicated as an example of molecular mimicry in the pathogenicity of autoimmune diseases and, more recently, in T cell-mediated protection. Curiously, in spite of this interest, the gene encoding HSP 60 has not yet been cloned. Sequencing of numerous PCR-derived HSP 60 clones. obtained following amplification of genomic DNA revealed multiple distinct but highly related sequences. These were all different from the sequence encoding the expressed protein and all had interrupted reading frames. PCR amplification from mRNA, however, yielded only the sequence expected for the expressed hsp 60 protein. This apparent paradox was resolved by cloning and sequencing HSP 60-specific genomic clones: the majority of these clones corresponded to intronless genes having the characteristics of retro-pseudogenes and were flanked by unrelated DNA sequences. In addition, several genomic clones were isolated that corresponded to a unique functional HSP 60 gene. This gene is composed of multiple exons, some very short. The transcription start site was identified and 750 bp of 5' flanking sequence were determined. The human HSP 60 gene is induced by heat. We conclude that hsp 60 is encoded by a single highly fragmented gene, that co-exists with multiple HSP 60 retro-pseudogenes, normally not expressed.