The Mechanism Of Gasdermin E-mediated Photoreceptor Damage By All-trans-retinal

Objective:This study focused on the mechanism of photoreceptor cell death induced by atRAL,explored the molecular mechanism of GSDME regulating neuroretinal degeneration,and revealed the cell death mechanism of neuroretinal degeneration more comprehensively.The breakdown of all-trans-retinal(atRAL)clearance is closely associated with photoreceptor cell death in dry age-related macular degeneration(AMD)and autosomal recessive Stargardt disease(STGD1),but its potential mechanisms remain elusive.In this study,we demonstrate that activation of gasdermin E(GSDME)but not gasdermin D(GSDMD)promotes atRAL-induced photoreceptor damage by activating pyroptosis and aggravating apoptosis through a mitochondria-mediated caspase-3-dependent signaling pathway.Activation of c-Jun N-terminal kinase(JNK)was identified as one of major causes of mitochondrial membrane rupture in atRAL-loaded photoreceptor cells,resulting in release of cytochrome c(Cyt c)from mitochondria to the cytosol,where it stimulated caspase-3 activation required for cleavage of GSDME.Aggregation of the N-terminal fragment of GSDME(GSDME-N)in the mitochondria revealed that GSDME was likely to directly penetrate mitochondrial membranes in photoreceptor cells following atRAL exposure.ABCA4 and RDH8 are two key proteins responsible for clearing atRAL in the retina.Abca4-/-Rdh8-/-mice exhibit serious defects in atRAL clearance upon light exposure,and serve as an acute model for dry AMD and STGD1.We found that GSDME-N was distinctly localized in the photoreceptor outer nuclear layer of light-exposed Abca4-/-Rdh8-/-mice.Of note,degeneration and caspase-3 activation in photoreceptors were significantly alleviated in Abca4-/-Rdh8-/-Gsdme-/mice after exposure to light.The results of this study indicate that GSDME is a common causative factor of both photoreceptor pyroptosis and apoptosis arising from atRAL overload,suggesting that repression of GSDME activation may represent a potential treatment of photoreceptor atrophy in dry AMD and STGD1.