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

Abstract

Necroptosis is an essential pathophysiological process in cerebral ischemia-related diseases. Therefore, targeting necroptosis may prevent cell death and provide a much-needed therapy. Ansiomycin is an inhibitor of protein synthesis which can also activate c-Jun N-terminal kinases. The present study demonstrated that anisomycin attenuated necroptosis by upregulating CHIP (carboxyl terminus of Hsc70-interacting protein) leading to the reduced levels of receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3) proteins in two in vitro models of cerebral ischemia. Further exploration in this research revealed that losing neither the co-chaperone nor the ubiquitin E3 ligase function of CHIP could abolish its ability to reduce necroptosis. Collectively, this study identifies a novel means of preventing necroptosis in two in vitro models of cerebral ischemia injury through activating the expression of CHIP, and it may provide a potential target for the further study of the disease.

CHIP as a therapeutic target for neurological diseases

“…In our study, CHIP protected N2a cells following oxygen glucose deprivation (OGD) through inhibiting necroptosis 30 . In detail, we detected upregulation of RIPK1, RIPK3, and MLKL in N2a cells exposed to OGD accompanied by increased cell death, and Nec-1, a RIPK1 inhibitor, could reverse these effects 30 . These results suggested that necroptosis was activated under OGD challenging.…”

“…Moreover, while other functions of anisomycin may contribute to the benefit of OGD, the role of CHIP may be much more important 30 . Neither the TPR nor the U-box domain of CHIP alone possesses the protective function of inhibiting necroptosis, suggesting that both the co-chaperone and ubiquitin E3 ligase functions of CHIP are necessary for anti-necroptosis following OGD 30 . Similarly, Cabral-Miranda et al reported that CHIP overexpression protected against hippocampal neuronal death through decreasing the phosphorylation of eIF2a and AKT in experimental brain ischemia 34 .…”

“…Several small-molecule agonists that can upregulate CHIP expression have been reported recently (Table 1) 30,68,78,79 . Sulforaphane, a herbal isothiocyanate draw from cruciferous vegetables, can clear the accumulation of Aβ and tau and then ameliorate learning and memory defaults in 3×Tg-AD mice through upregulating CHIP expression in the cortex and hippocampus 68 .…”

“…Hence, developing new therapeutic agents is urgently needed. Recent studies have demonstrated that CHIP participates in the pathological process of ischemic stroke; interestingly, the implicated mechanisms vary 30 – 34 . Anderson et al reported that CHIP expression is upregulated in the postmortem brain tissues of patients after stroke 31 , implying that CHIP may play an important role in the pathological mechanism after stroke and may be a potential therapeutic target for neuronal injury.…”

“…As expected, CHIP overexpression could reduce the RIPK3 level by post-translational regulation under OGD-challenging. Moreover, while other functions of anisomycin may contribute to the benefit of OGD, the role of CHIP may be much more important 30 . Neither the TPR nor the U-box domain of CHIP alone possesses the protective function of inhibiting necroptosis, suggesting that both the co-chaperone and ubiquitin E3 ligase functions of CHIP are necessary for anti-necroptosis following OGD 30 .…”