Negative Regulation of the Novel norpAP24 Suppressor, diehard4, in the Endo-lysosomal Trafficking Underlies Photoreceptor Cell Degeneration

Abstract

Rhodopsin has been used as a prototype system to investigate G protein-coupled receptor (GPCR) internalization and endocytic sorting mechanisms. Failure of rhodopsin recycling upon light activation results in various degenerative retinal diseases. Accumulation of internalized rhodopsin in late endosomes and the impairment of its lysosomal degradation are associated with unregulated cell death that occurs in dystrophies. However, the molecular basis of rhodopsin accumulation remains elusive. We found that the novel norpAP24 suppressor, diehard4, is responsible for the inability of endo-lysosomal rhodopsin trafficking and retinal degeneration in Drosophila models of retinal dystrophies. We found that diehard4 encodes Osiris 21. Loss of its function suppresses retinal degeneration in norpAP24, rdgC306, and trp1, but not in rdgB2, suggesting a common cause of photoreceptor death. In addition, the loss of Osiris 21 function shifts the membrane balance between late endosomes and lysosomes as evidenced by smaller late endosomes and the proliferation of lysosomal compartments, thus facilitating the degradation of endocytosed rhodopsin. Our results demonstrate the existence of negative regulation in vesicular traffic between endosomes and lysosomes. We anticipate that the identification of additional components and an in-depth description of this specific molecular machinery will aid in therapeutic interventions of various retinal dystrophies and GPCR-related human diseases.

Genetic basis of octanoic acid resistance inDrosophila sechellia: functional analysis of a fine‐mapped region

“…; Lee et al . ). Beyond these sequence‐based predictions, Osi6 , Osi7 and Osi8, all remain functionally uncharacterized.…”

“…; Lee et al . ). The only member of this gene family that has been functionally characterized is Osi21, and a recent study found that diehard4, a norpA P24 suppressor, is encoded by Osi21 (Lee et al .…”

“…The only member of this gene family that has been functionally characterized is Osi21, and a recent study found that diehard4, a norpA P24 suppressor, is encoded by Osi21 (Lee et al . ). Detailed molecular analysis showed that Osi21 has a critical role in membrane homoeostasis between the endosomes and lysosomes in eye cells.…”

“…Ultimately, they found that Osi21 acts as a negative regulator of late endosomal membrane traffic to the lysosome and that loss of Osi21 function facilitates toxin traffic towards the lysosome and eventual lysosomal degradation of that toxin (Lee et al . ). Extreme sequence similarity between Osi21 and Osi6 , Osi7 and Osi8 (Dorer et al .…”

Investigating the role ofOsirisgenes inDrosophila sechellialarval resistance to a host plant toxin

“…For example, Yassin et al () conducted a population genomics scan between an island specialist population of D. yakuba that recently specialized on Morinda citrifolia and a mainland generalist population of the same species and found that one of the strongest differentiation peaks mapped to the Osiris cluster on chromosome 3R (Yassin et al, ) possibly illustrating a case of parallel evolution through this locus. Only one other Osiris gene, Osi21 , has been functionally tested in D. melanogaster and loss‐of‐function alleles of this gene shift membrane balance between late endosomes and lysosomes facilitating degradation of endocytosed rhodopsin in eye cells (Lee, Song, & Hong, ). This finding is interesting as it suggests Osiris genes may be involved in detoxification.…”