IRF1-triggered ZBP1 Transcription Mediates Cell Death of Neurons

Neurodegenerative disease (ND) characterized by progressive neuronal cell death is closely associated with excessive production of TNF-α in the cerebrum. However, the specific molecular mechanism linking TNF-α and neuronal cell death remains to be fully elucidated. Here, we report that TNF-α-induced expression of ZBP1 plays a central role in neuronal cell death. We further demonstrate that IRF1 activates ZBP1 expression by directly binding to a core regulatory motif in the ZBP1 promoter in murine neuronal cells but not microglial cells. Moreover, the binding of IRF1 to the ZBP1 promoter causes the increase in ZBP1 expression in two human cell lines. Importantly, the expression levels of IRF1 and ZBP1 are positively correlated in TNF-α-related neurodegenerative disease, suggesting that the TNF-α-IRF1-ZBP1 axis may be a previously unrecognized mechanism of neuronal cell death in neurodegenerative diseases. Our study expands the knowledge on the upstream regulators that induce ZBP1 transcription and provides new insight into the role of ZBP1 in neurodegenerative diseases.