A DIVERGENT MULTIDOMAIN CYCLOPHILIN IS HIGHLY CONSERVED BETWEEN PARASITIC AND FREE-LIVING NEMATODE SPECIES AND IS IMPORTANT IN LARVAL MUSCLE DEVELOPMENT

A divergent multi-domain cyclophilin from the filarial nematodes Brugi a malayi, Onchocerca volvulus and Dirofilaria immitis has a highly con served orthologue in the free-living nematodes Caenorhabditis elegans and C. briggsae. Cyclophilins are the receptors for the immunosuppress ive and anti-parasitic agent cyclosporin A and additionally these ubiq uitously expressed proteins have protein folding capabilities, and exh ibit proline isomerase activity. These divergent nematode cyclophilins (CYP-4 isoforms) are three domain proteins, which share 63-88% identi ty and have highly conserved differences present in their functionally important cyclosporin A binding and proline isomerase domains. This u nusual class of nematode cyclophilins has been studied in the model ne matode C. elegans, revealing a unique temporal and spatial expression pattern. The cyp-4 transcript is most abundantly expressed in the earl y larval stages and is expressed exclusively in the body-wall striated muscle cells. An important functional role was established for this d ivergent enzyme, as specific double-stranded RNA interference experime nts resulted in progeny with a phenotypically lumpy appearance. This m orphological defect was predominantly expressed in the early larval st ages and is consistent with an effect on body-wall muscle cell develop ment. This study has established that this highly conserved family of nematode cyclophilins has a tissue-specific, functional role in early larval development and supports the use of C. elegans as a model for t he study of orthologues in the experimentally less amenable parasitic nematodes. (C) 1998 Elsevier Science B.V. All rights reserved.