REEP6 deficiency impairs ER and Golgi morphologies and causes retinal degeneration by attenuating the expression of phototransduction proteins

Abstract

REEP6 is a member of the REEP family proteins belonging to the YIP superfamily. REEP proteins were membrane proteins involved in regulating membrane curvature. Mutations in REEP6 are associated with retinitis pigmentosa (RP). Mice lacking REEP6 were generated to model human RP. Reep6 mutant mice exhibit progressive retinal degeneration, which is attributed to abnormal trafficking of PDE6 and the absent expression of guanylate cyclases (GCs), due to ER dysfunction. However, the phenotype regarding the failed expression of GCs is questionable. Here, we generated an independent Reep6 knockout mouse model. Our Reep6-deficient mouse line showed progressive retinal degeneration as previously reported. Nevertheless, unlike the previous report, our Reep6 mutant mice had normal trafficking of PDE6. GCs were not absent from the mutant mice, but their expression decreased by approximately one third. Other membrane phototransduction proteins, such as rhodopsin and rhodopsin kinase (GRK1) were also reduced. Attenuated expression of membrane proteins might stem from abnormal ER and Golgi function, as in vitro expression of REEP6 altered the expression of the ER marker and Golgi morphologies. Additionally, RNA-seq revealed that deletion of Reep6 caused reduced expression of multiple phototransduction proteins at the transcription level and activated the inflammation pathway. Thus, retinal degeneration associated with REEP6 mutations is the consequence of reduced expression of phototransduction proteins mediated by ER and Golgi dysfunction and ensuing retinal inflammation.