Title: RSK3 mediates necroptosis by regulating RIP3 activity in retinal ganglion cells

Kun Xiong

Xiangya Medical School, Central South University, China


Kun Xiong, MD, PhD, Professor, Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, China. Field of Specialization: Neurobiology of neural njury/regeneration; he is the academic editor of Editorial Board of Medicine and Neural Regeneration Research. He has supported by 3 grants from National Natural Science Foundation of China, and published more than 30 articles about neuroscience in International academic journal.


Receptor-interacting protein 3 (RIP3) plays an important role in the necroptosis signalling pathway. Our previous studies have shown that RIP3/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis occurred in retinal ganglion cell line 5 (RGC-5) cells during oxygen-glucose deprivation (OGD) injury. However, the upstream regulating pathways of RIP3 have yet to be uncovered. The purpose of the current study was to investigate the role of ribosomal protein S6 kinase 3 (RSK3) in the phosphorylation of RIP3 in RGC-5 cells during necroptosis following OGD injury. First, we found that the expression of RSK3, RIP3/p-RIP3, and MLKL/p-MLKL was upregulated and that the necroptosis of RGC-5 cells was elevated after OGD injury. Then, we performed a preliminary computer simulation to evaluate whether RSK3 could interact with RIP3, and later confirmed this interaction by co-immunoprecipitation. Furthermore, we found that the application of a specific RSK3 inhibitor, LJH685, or rsk3-siRNA decreased the phosphorylation of RIP3, while over-expressing rip3 did not affect the expression of RSK3, which indicates that RSK3 is an upstream regulator of RIP3 during the necroptosis induced by OGD in RGC-5 cells. Finally, in vivo studies with rats showed that pretreatment with LJH685 before acute high intraocular pressure episodes reduced the necroptosis of retinal neurons and improved the recovery of impaired visual function. Taken together, our findings suggested that RSK3 is one of the key upstream regulatory molecules in RIP3 phosphorylation during RGC-5 necroptosis.