THE CYCLOPHILIN HOMOLOG NINAA FUNCTIONS AS A CHAPERONE, FORMING A STABLE COMPLEX IN-VIVO WITH ITS PROTEIN TARGET RHODOPSIN

In Drosophila, biogenesis of the major rhodopsin, Rh1, is dependent on the presence of a photoreceptor cell-specific cyclophilin, NinaA. In ninaA mutants, Rh1 is retained within the endoplasmic reticulum and rh odopsin levels are reduced >100-fold. Cyclophilins have been shown to be peptidyl-prolyl cis-trans isomerases and have been implicated in ca talyzing protein folding. We have generated transgenic animals express ing different functional rhodopsins containing a histidine tag. We iso lated these molecules from wild-type and ninaA mutant retinas, and hav e demonstrated that in vivo NinaA forms a specific stable protein comp lex with its target Rh1. We also expressed ninaA under an inducible pr omoter and showed that NinaA is required quantitatively for Rh1 biogen esis. These results provide the first evidence for a biologically rele vant physical interaction between a cyclophilin and its cellular targe t, and suggest that the normal cellular role of this class of cyclophi lins is to function as chaperones, possibly escorting their protein su bstrates through the secretory pathway.