title: GS28 Protects Neuronal Cell Death Induced by Hydrogen Peroxide under Glutathione-Depleted Condition.
abstract: Golgi SNAP receptor complex 1 (GS28) has been implicated in vesicular transport between intra-Golgi networks and between endoplasmic reticulum (ER) and Golgi. Additional role(s) of GS28 within cells have not been well characterized. We observed decreased expression of GS28 in rat ischemic hippocampus. In this study, we examined the role of GS28 and its molecular mechanisms in neuronal (SK-N-SH) cell death induced by hydrogen peroxide (H(2)O(2)). GS28 siRNA-transfected cells treated with H(2)O(2) showed a significant increase in cytotoxicity under glutathione (GSH)-depleted conditions after pretreatment with buthionine sulfoximine, which corresponded to an increase of intracellular reactive oxygen species (ROS) in the cells. Pretreatment of GS28 siRNA-transfected cells with p38 chemical inhibitor significantly inhibited cytotoxicity; we also observed that p38 was activated in the cells by immunoblot analysis. We confirmed the role of p38 MAPK in cotransfected cells with GS28 siRNA and p38 siRNA in the cell viability assay, flow cytometry, and immunoblot. Involvement of apoptotic or autophagic processes in the cells was not shown in the cell viability, flow cytometry, and immunoblot analyses. However, pretreatment of the cells with necrostatin-1 completely inhibited H(2)O(2)-induced cytotoxicity, ROS generation, and p38 activation, indicating that the cell death is necroptotic. Collectively these data imply that H(2)O(2) induces necroptotic cell death in the GS28 siRNA-transfected cells and that the necroptotic signals are mediated by sequential activations in RIP1/p38/ROS. Taken together, these results indicate that GS28 has a protective role in H(2)O(2)-induced necroptosis via inhibition of p38 MAPK in GSH-depleted neuronal cells.
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Hwa Ok
authors.initials: HO
authors.lastname: Lee
authors.forename: Yu Jeong
authors.initials: YJ
authors.lastname: Byun
authors.forename: Kyung-Ok
authors.initials: KO
authors.lastname: Cho
authors.forename: Seong Yun
authors.initials: SY
authors.lastname: Kim
authors.forename: Seong-Beom
authors.initials: SB
authors.lastname: Lee
authors.forename: Ho-Shik
authors.initials: HS
authors.lastname: Kim
authors.forename: Oh-Joo
authors.initials: OJ
authors.lastname: Kwon
authors.forename: Seong-Whan
authors.initials: SW
authors.lastname: Jeong