ZBP1-Mediated Necroptosis: Mechanisms and Therapeutic Implications
Xin-Yu Chen1, Ying-Hong Dai1,2, Xin-Xing Wan3
1Department of Human Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 430013, China.
Abstract:
Cell death is a fundamental pathophysiological process in human disease. The discovery of necroptosis, a form of regulated necrosis that is induced by the activation of death receptors and formation of necrosome, represents a major breakthrough in the field of cell death in the past decade. Z-DNA-binding protein (ZBP1) is an interferon (IFN)-inducing protein, initially reported as a double-stranded DNA (dsDNA) sensor, which induces an innate inflammatory response. Recently, ZBP1 was identified as an important sensor of necroptosis during virus infection. It connects viral nucleic acid and receptor-interacting protein kinase 3 (RIPK3) via two domains and induces the formation of a necrosome. Recent studies have also reported that ZBP1 induces necroptosis in non-viral infections and mediates necrotic signal transduction by a unique mechanism. This review highlights the discovery of ZBP1 and its novel findings in necroptosis and provides an insight into its critical role in the crosstalk between different types of cell death, which may represent a new therapeutic option.
Insights
Z-DNA-binding protein (ZBP1) is a key sensor for necroptosis, a regulated cell death. Recent findings reveal ZBP1
Area of Science:
- Cellular biology
- Immunology
- Molecular mechanisms of cell death
Background:
- Cell death is crucial in human disease pathogenesis.
- Necroptosis, a regulated form of necrosis, has emerged as a significant area of study.
- Z-DNA-binding protein (ZBP1) was initially identified as an interferon-inducing dsDNA sensor.
Purpose of the Study:
- To review the discovery and novel findings of ZBP1 in necroptosis.
- To explore ZBP1's role in sensing viral and non-viral triggers of necroptosis.
- To provide insights into ZBP1's function in the interplay between different cell death pathways.
Main Methods:
- Literature review of recent studies on ZBP1 and necroptosis.
- Analysis of ZBP1's molecular domains and signaling pathways.
- Examination of ZBP1's role in viral and non-viral infection models.
Main Results:
- ZBP1 acts as a critical sensor linking nucleic acids to necroptosis induction.
- ZBP1 mediates necroptosis through interaction with RIPK3, forming the necrosome.
- ZBP1 has been shown to induce necroptosis in response to both viral and non-viral stimuli.
Conclusions:
- ZBP1 plays a pivotal role in regulating necroptosis.
- ZBP1's function extends beyond viral infections, impacting non-viral scenarios.
- Understanding ZBP1's role in cell death crosstalk may offer new therapeutic strategies.
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