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RSK3 mediates necroptosis by regulating phosphorylation of RIP3 in rat retinal ganglion cells |
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| Authors: | Mi Wang Hao Wan Shuchao Wang Lvshuang Liao Yanxia Huang Limin Guo Fengxia Liu Lei Shang Jufang Huang Dan Ji Xiaobo Xia Bin Jiang Dan Chen Kun Xiong |
| Affiliation: | 1. Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, China;2. Department of Human Anatomy, School of Basic Medical Science, Xinjiang Medical University, Urumqi, China;3. Jiangxi Research Institute of Ophthalmology and Visual Sciences, Affiliated Eye Hospital of Nanchang University, Nanchang, China;4. Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, China Hunan Key Laboratory of Ophthalmology, Changsha, China;5. Hunan Key Laboratory of Ophthalmology, Changsha, China Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China;6. Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China |
| Abstract: | Receptor-interacting protein 3 (RIP3) plays an important role in the necroptosis signaling pathway. Our previous studies have shown that the RIP3/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis occurs in retinal ganglion cell line 5 (RGC-5) following oxygen-glucose deprivation (OGD). However, upstream regulatory pathways of RIP3 are yet to be uncovered. The purpose of the present study was to investigate the role of p90 ribosomal protein S6 kinase 3 (RSK3) in the phosphorylation of RIP3 in RGC-5 cell necroptosis following OGD. Our results showed that expression of RSK3, RIP3, and MLKL was upregulated in necroptosis of RGC-5 after OGD. A computer simulation based on our preliminary results indicated that RSK3 might interact with RIP3, which was subsequently confirmed by co-immunoprecipitation. Further, we found that the application of a specific RSK inhibitor, LJH685, or rsk3 small interfering RNA (siRNA), downregulated the phosphorylation of RIP3. However, the overexpression of rip3 did not affect the expression of RSK3, thereby indicating that RSK3 could be a possible upstream regulator of RIP3 phosphorylation in OGD-induced necroptosis of RGC-5 cells. Moreover, our in vivo results showed that pretreatment with LJH685 before acute high intraocular pressure episodes could reduce the necroptosis of retinal neurons and improve recovery of impaired visual function. Taken together, our findings suggested that RSK3 might work as an upstream regulator of RIP3 phosphorylation during RGC-5 necroptosis. |
| Keywords: | necroptosis oxygen and glucose deprivation p90 ribosomal protein S6 kinase 3 phosphorylation receptor-interacting proteins 3 retinal ganglion cell-5 |