Photoreceptor cell death triggered by rhodopsin aggregation requires immunity signaling and transcriptional activation through NF-kB. Patrick J. Dolph, Ron Kinser, Yashodhan Chinchore. Biological Sciences, Dartmouth College, Hanover, NH.

   Retinitis pigmentosa (RP) is a common retinal disease characterized by an age-related progressive loss of vision. Specific forms of RP are typified by the abnormal localization of the light receptor rhodopsin to cytoplasmic compartments. We have been able to phenocopy this form of RP in Drosophila. We have identified mutations that induce retinal degeneration and are characterized by the massive internalization of rhodopsin via receptor-mediated endocytosis. This internalized rhodopsin is not degraded in the endolysosomal system but instead accumulates in the late endosome where it forms insoluble aggregates. Genetic analysis has revealed that this mislocalized aggregated rhodopsin does not trigger cell death through any of the classical apoptotic pathways. Instead, we found that cell death requires components of the innate immunity pathway eventually leading to the activation of NF-kB transcription factors. Interestingly, mutations affecting both the Toll signaling pathway and the Imd pathway rescue retinal degeneration in our model and two different NF-kB orthologues, Relish and Dorsal, are also both required. In addition, we have show that expression of an activated form of Relish or the induction of the Toll pathway in photoreceptors and other cell types triggers cell death, suggesting that these protective pathways may induce apoptosis in specific cell types. These results define a new role for innate immunity signaling and NF-kB transcription factors in cell death induction.