USP43 promotes cerebral ischemia-reperfusion injury via activation of TAK1.

BACKGROUND

Neuroinflammation and apoptosis are important processes of cerebral ischemia-reperfusion injury. USP43 has been shown to play an important role in a variety of cancers, but its function in the field of neuroscience is unclear.

RESULTS

We used an ischemia-reperfusion model of transient embolization of the middle cerebral artery in mice and found that USP43 protein expression was elevated in mice after ischemia-reperfusion injury. Usp43 knockout reduced cerebral infarct volume, inflammatory response, and cell apoptosis, compared to control mice. In vitro, we used an oxygen-glucose-deprived primary neuronal model of rat cortex. Compared with the control group, the Usp43 knockdown group had better cell activity, and the inflammatory response and apoptosis were reduced. Cells in the Usp43 overexpression group exhibited the opposite performance. Mechanistically, we found that USP43 directly interacts with TAK1 by exerting its function as a deubiquitinating enzyme, removing the K48 chain ubiquitination of TAK1 and activating the TAK1-JNK/p38 signaling pathway. Inhibition of USP43 enzyme activity or the use of TAK1 inhibitors can reverse the inflammatory response and neuronal apoptosis induced by USP43 overexpression.

CONCLUSIONS

These results suggest that USP43 promotes I-R damage by activating TAK1 and its downstream signaling pathways. Inhibition of USP43 may be a potential treatment modality for acute stroke.