...Given that autophagy in the RPE suppresses waste accumulation, determining the molecular mechanism by which autophagy is compromised in degeneration is necessary. Using polarized human RPE sheets, we found that bis-retinoid N-retinyl-N-retinylidene ethanolamine (A2E), a major toxic fluorophore of lipofuscin, causes significant impairment of autophagy and the simultaneous upregulation of Rubicon, a negative regulator of autophagy. Importantly, this impairment was reversed in Rubicon-specific siRNA-treated RPE sheets. In a retinal functional analysis using electroretinograms (ERGs), mice with the RPE-specific deletion of Rubicon showed no significant differences from control cre-expressing mice but presented partially but significantly enhanced amplitudes compared with Atg7 knockout mice. We also found that an inflammatory reaction in the retina in response to chronic blue light irradiation was alleviated in mice with the RPE-specific deletion of Rubicon. In summary, we propose that upregulating basal autophagy by targeting Rubicon is beneficial for protecting the RPE from functional damage with ageing and the inflammatory reaction caused by light-induced cellular stress.