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A Motor Neuron Disease-Associated Mutation Produces Non-Glycosylated Seipin That Induces ER Stress and Apoptosis by Inactivating SERCA2b
Shunsuke Saito and Kazutoshi Mori
Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
Accumulating evidence from cellular analysis with pharmacological approach indicated that persistent endoplasmic reticulum (ER) stress impairs important cellular functions and may even lead to cell death, however, the causal relationship between such ER stress and neurodegeneration remains unclear. Here, we focused on the ER membrane protein non-glycosylated Seipin (ngSeipin) encoded by a mutant gene that causes Seipinopathy, a dominant motor neuron disease. Previous report showed that Seipin evokes ER stress in the brain of transgenic mice albeit no clarified mechanism (Yagi et al., Hum. Mol. Genet., 2011). Inspired by the finding that Drosophila Seipin binds to SERCA (sarco/endoplasmic reticulum Ca2+-ATPase) and promotes calcium ion uptake into the ER (Bi et al., Cell Metab., 2014), we examined whether Seipin affects the store of calcium ion in the ER. We found that expression of Seipin by transfection in HCT116, a human diploid cell line from colorectal carcinoma, decreases calcium ion concentration in the ER in a dose-dependent manner, resulting in induction of ER stress and subsequent cell death. We observed similar effects in Seipin-knockout human neuroblastoma cell line SH-SY5Y expressing endogenous level of Seipin. It is because Seipin oligomerization-dependent formation of aggregates incorporates and inactivates SERCA2b. Finally, we found that expression of SERCA2b together with Seipin compensates for the reduced calcium ion concentration in the ER, thereby attenuating ER stress and cell death. These results demonstrate that Seipin directly inhibits the function of SERCA2b, one of the major molecules responsible for calcium ion homeostasis in the ER, leading to ER stress and cell death (Saito et al., eLife, 2022). This molecular mechanism should account for the development of Seipinopathy.
Speakers
Shunsuke Saito