The Retromer Complex Is Required for Rhodopsin Recycling and Its Loss Leads to Photoreceptor Degeneration

Abstract

Rhodopsin recycling via the retromer, rather than degradation through lysosomes, can alleviate light-induced photoreceptor degeneration in Drosophila.

Abstract

Rhodopsin mistrafficking can cause photoreceptor (PR) degeneration. Upon light exposure, activated rhodopsin 1 (Rh1) in Drosophila PRs is internalized via endocytosis and degraded in lysosomes. Whether internalized Rh1 can be recycled is unknown. Here, we show that the retromer complex is expressed in PRs where it is required for recycling endocytosed Rh1 upon light stimulation. In the absence of subunits of the retromer, Rh1 is processed in the endolysosomal pathway, leading to a dramatic increase in late endosomes, lysosomes, and light-dependent PR degeneration. Reducing Rh1 endocytosis or Rh1 levels in retromer mutants alleviates PR degeneration. In addition, increasing retromer abundance suppresses degenerative phenotypes of mutations that affect the endolysosomal system. Finally, expressing human Vps26 suppresses PR degeneration in Vps26 mutant PRs. We propose that the retromer plays a conserved role in recycling rhodopsins to maintain PR function and integrity.

Author Summary

Upon light exposure, rhodopsins—light-sensing proteins in the eye—trigger visual transduction signaling to activate fly photoreceptor cells. After activation, rhodopsins can be internalized from the cell surface into endosomes and then degraded in lysosomes. This mechanism prevents constant activation of the visual transduction pathway, thereby maintaining the function and integrity of photoreceptor cells. It is not known, however, whether these internalized rhodopsins can be recycled. Here, we show that the retromer, an evolutionarily conserved protein complex, is required for the recycling of rhodopsins. We find that loss of key retromer subunits (Vps35 or Vps26) causes rhodopsin mislocalization in the photoreceptors and severe light-induced photoreceptor degeneration. Conversely, gain of retromer subunits can alleviate photoreceptor degeneration in some contexts. Human retromer components can stand in for depleted fruit fly retromer, suggesting that this complex plays a role in recycling light sensors in both vertebrate and invertebrate photoreceptors.