A Molecular Pathway for Light-Dependent Photoreceptor Apoptosis in Drosophila

Abstract

Light-induced photoreceptor apoptosis occurs in many forms of inherited retinal degeneration resulting in blindness in both vertebrates and invertebrates. Though mutations in several photoreceptor signaling proteins have been implicated in triggering this process, the molecular events relating light activation of rhodopsin to photoreceptor death are yet unclear. Here, we uncover a pathway by which activation of rhodopsin in Drosophila mediates apoptosis through a G protein-independent mechanism. This process involves the formation of membrane complexes of phosphorylated, activated rhodopsin and its inhibitory protein arrestin, and subsequent clathrin-dependent endocytosis of these complexes into a cytoplasmic compartment. Together, these data define the proapoptotic molecules in Drosophila photoreceptors and indicate a novel signaling pathway for light-activated rhodopsin molecules in control of photoreceptor viability.

Phototransduction and retinal degeneration in Drosophila

“…If the flies are maintained in the dark ∼80% of the major arrestin (Arr2) and nearly all of the minor arrestin (Arr1) are localized to the cell bodies; however, after ∼5 min of light exposure, most of the arrestin moves into the rhabdomeres (Fig. 7a) [97,99]. This phenomenon of light-dependent translocation of arrestin was first described in mammalian rods [178][179][180][181].…”

“…Nevertheless, Arr1 may also participate in deactivation since termination is more severe when both arr1 and arr2 are mutated [95]. Unlike the case with the vertebrate rhodopsins, the binding of Arr2 to Rh1 is not dependent on phosphorylation of Rh1 [96][97][98]. However, phosphorylation of the C terminus of rhodopsin contributes to Arr1 binding and this interaction promotes endocytosis of Rh1, which is proposed to play a role in scavenging spontaneously activated, phosphorylated metarhodopsin [99].…”

“…Mutations such as those in trp and norpA that prevent the normal rise in Ca 2+ after light stimulation result in stable Rh1/Arr2 complexes and retinal degeneration. Elimination of the rhodopsin phosphatase, RDGC, also promotes stable Rh1/Arr2 complexes [97]. Disruption of Rh1/Arr2 stable complexes either in norpA, trp or rdgC, by genetic removal of Arr2, suppresses the retinal degeneration.…”

“…Mutation of the dynamin GTPase (shibire), which prevents clathrin-mediated endocytosis, suppresses the retinal degeneration in the rdgC mutant [97]. Loss of the α subunit of AP-2 adaptor complex has been shown to suppress the retinal degeneration in the norpA mutant [223].…”

Sphingolipids and membrane biology as determined from genetic models

“…They also facilitate the endocytic turnover of light-activated Rhodopsin. In Arrestin mutants, the photoreceptors degenerate because of endocytic defects [58][59][60]. In these mutants, chronically active rhodopsin leads to increased calcium entry, calcium necrotoxicity, and the defective endocytosis of rhodopsin.…”