Breaking News: Caspase-8 Acts as a Molecular Switch for Apoptosis, Necroptosis and Pyroptosis

1. Background of Caspase-8 Research

Caspase-8, a key member of the cysteine aspartate-specific protease (Caspase) family, has long been known for its role in initiating extrinsic apoptosis. Previous studies have clearly demonstrated that Caspase-8 can inhibit necroptosis mediated by RIPK3 (Receptor-Interacting Protein Kinase 3) and MLKL (Mixed Lineage Kinase Domain-Like Protein). A typical manifestation of this regulatory function is that Caspase-8-deficient mice suffer from embryonic lethality, which can be rescued by knockout of RIPK3 or MLKL. This finding initially revealed the important regulatory role of Caspase-8 in the balance between apoptosis and necroptosis.

However, with the in-depth study of pyroptosis—a pro-inflammatory programmed cell death mode characterized by cell membrane pore formation, swelling, and release of pro-inflammatory factors such as IL-1β and IL-18—the potential regulatory role of Caspase-8 in pyroptosis has gradually attracted attention. The latest research published in Nature further clarifies the multi-faceted regulatory role of Caspase-8 in different cell death pathways, opening up new horizons for understanding the complex network of cell death regulation.

2. Core Findings of the Latest Research

Through detailed gene-edited animal experiments and in vitro cellular studies, the research team systematically explored the regulatory mechanism of Caspase-8 in cell death pathways. The core findings are as follows:

•         Caspase-8 enzyme activity determines cell death fate: The study found that the expression of Caspase-8 with low enzyme activity in mice leads to embryonic lethality, which is achieved by inducing both necroptosis and pyroptosis. This indicates that the enzyme activity of Caspase-8 is a key determinant of cell death direction—sufficient enzyme activity promotes apoptosis, while insufficient enzyme activity shifts the cell death mode to necroptosis and pyroptosis.

•         MLKL knockout rescues embryonic lethality: Further experiments showed that knockout of MLKL, a key executor of necroptosis, can rescue the embryonic and perinatal death of gene-edited mice with low Caspase-8 enzyme activity. This result confirms that when the necroptosis pathway is blocked, Caspase-8-mediated regulation of other pathological tissue processes (such as pyroptosis) is also affected, highlighting the interactive regulation between different cell death pathways centered on Caspase-8.

3. Molecular Mechanism of Caspase-8 as a "Molecular Switch"

The regulatory role of Caspase-8 as a molecular switch is closely related to its interaction with key molecules in different cell death pathways and its ability to cleave specific substrates:

•         Regulation of apoptosis: As an initiator of extrinsic apoptosis, Caspase-8 is recruited to the death-inducing signaling complex (DISC) formed by death receptors, undergoes autoactivation, and then triggers the downstream Caspase cascade reaction, ultimately leading to apoptosis.

•         Inhibition of necroptosis: Caspase-8 can cleave RIPK1 and RIPK3, key molecules in the necroptosis pathway, thereby blocking the formation of the necrosome and inhibiting the activation of MLKL, thus suppressing necroptosis.

•         Regulation of pyroptosis: Recent studies have shown that Caspase-8 can cleave gasdermin family proteins (such as GSDMD, GSDMC) under specific conditions (e.g., Yersinia infection, hypoxia), releasing their N-terminal domain which forms pores on the cell membrane, thereby inducing pyroptosis. The low enzyme activity of Caspase-8 may alter its substrate specificity, favoring the cleavage of pyroptosis-related substrates.

4. Significance of the Research

This research not only clarifies the new role of Caspase-8 as a molecular switch regulating multiple cell death pathways but also provides important theoretical basis for understanding the occurrence and development of various diseases. Abnormal regulation of cell death is closely related to the pathogenesis of inflammation, infection, tumors, neurodegenerative diseases, and other diseases. For example, the overactivation of necroptosis and pyroptosis can lead to excessive inflammation and tissue damage, while the dysregulation of apoptosis may promote tumorigenesis. Therefore, targeting Caspase-8 and its related pathways may become a new strategy for the treatment of these diseases.

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7. Disclaimer

This article is compiled and interpreted by AI based on the original work published in Nature (DOI: https://www.nature.com/articles/s41586-019-1770-6). All intellectual property rights (such as data, conclusions) of the original publication belong to the journal and the research team. For any infringement, please contact us immediately and we will take prompt action.

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