Gasdermin E mediates photoreceptor damage by all-trans-retinal in the mouse retina

• Published in: The Journal of biological chemistry 2022-02, Vol.298 (2), p.101553-101553, Article 101553
• Main Authors: Cai, Binxiang, Liao, Chunyan, He, Danxue, Chen, Jingmeng, Han, Jiahuai, Lu, Jiaying, Qin, Kaiqi, Liang, Wenxu, Wu, Xiaoling, Liu, Zuguo, Wu, Yalin
• Format: Article
• Language: English
• Subjects: age-related macular degeneration; Animals; apoptosis; ATP-Binding Cassette Transporters - metabolism; c-Jun N-terminal kinase; Caspase 3 - metabolism; gasdermin E; Mice; photoreceptor; Photoreceptor Cells - metabolism; Photoreceptor Cells - pathology; Pore Forming Cytotoxic Proteins - metabolism; pyroptosis; reactive oxygen species; Retina - metabolism; Retina - pathology; Retinaldehyde - metabolism; Stargardt Disease - metabolism; Stargardt Disease - pathology; Stargardt's disease
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2021.101553

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's disease (STGD1), but its mechanisms remain elusive. Here, we demonstrate that activation of gasdermin E (GSDME) but not gasdermin D 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 was identified as one of the major causes of mitochondrial membrane rupture in atRAL-loaded photoreceptor cells, resulting in the release of cytochrome 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 in the mitochondria revealed that GSDME was likely to penetrate mitochondrial membranes in photoreceptor cells after atRAL exposure. ABC (subfamily A, member 4) and all-trans-retinol dehydrogenase 8 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 N-terminal fragment of GSDME 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 photoreceptor pyroptosis and apoptosis arising from atRAL overload, suggesting that repressing GSDME may represent a potential treatment of photoreceptor atrophy in dry AMD and STGD1.