Anisomycin prevents OGD-induced necroptosis by regulating the E3 ligase CHIP

Necroptosis is a form of caspase-independent cell death, pathologically characterized by a gain in cell volume, swelling of organelles, plasma membrane rupture, and subsequent loss of intracellular contents. Receptor-interacting protein kinase 1 (RIPK1), Receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) play critical roles in the pathological activation of necroptosis. The type of cell death that ensues cerebral ischemia may include different programmed cell death mechanisms namely oxidative stress, ion balance disorder, calcium overload, apoptosis and necroptosis. Studies have revealed that necroptosis contributed to the selective and delayed death of certain populations of neurons that occurs following an ischemic stroke, which can be caused by a lack of blood supply to the brain. Necroptosis has also been implicated in ischemic necrosis of retinal cells in several studies. Oxygen-glucose deprivation (OGD), an in vitro model of cerebral ischemia, can also induce the death receptor (DR)-dependent component of necroptotic cell death in cultured neurons, concomitant with the increase in RIPK3/RIPK1 mRNA and protein levels. Similar phenomenons have been also detected in an in vivo model of transient global cerebral ischemia, specifically in the CA1 area. These lines of evidence point to inhibiting necroptosis as a novel therapeutic strategy for cerebral ischemic injury, which represents the second leading cause of death as well as the leading cause of premature death and disability. Continued development of therapeutic options for ischemic stroke is woefully needed. C-terminus of HSC70-interacting protein (CHIP) is a 35-kDa protein that functions as both a molecular or autonomous chaperone and ubiquitin E3 ligase. Previous studies have demonstrated that the TPR domain of CHIP underlined its cochaperone function, whereas the U-box domain of CHIP mediated its ubiquitin E3 ligase function. The function of CHIP is proposed to behave as protective factor by degrading the abnormal folded proteins. Specifically, CHIP plays critical roles in the regulation of cell growth, apoptosis, neurodegeneration, invasion, stem cell differentiation, and cardiac fibrosis. Study in the central nervous system indicated that overexpression of CHIP attenuated ER-stress death response while maintain ER stress adaptative response. In brain ischemia, transfer of CHIP could prevent hippocampal neuronal death. Recent studies have revealed that CHIP controls necroptosis through the ubiquitination and lysosome-dependent degradation of RIPK3 and RIPK1. However, the role of CHIP in the necroptosis induced by OGD have not been described.