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The balance between death and life: How does Daxx play dual roles of anti-apoptosis and pro-apoptosis in cells?
In the world of cell biology, proteins often play more than superficial roles. Death-associated protein 6 (Daxx) is a typical example that can freely move between anti-apoptotic and pro-apoptotic. Daxx is encoded by the DAXX gene, a protein that plays a key role in regulating cell death and growth.
Function and structure of Daxx
Daxx is a multifunctional protein originally discovered for its cytoplasmic interaction with the classical death receptor Fas. Daxx not only exists in the nucleus and cytoplasm, but is also associated with heterochromatin and erythrocytic leukemia nuclear bodies (PML-NBs) and is thought to play an important role in multiple nuclear processes such as transcription and cell cycle regulation.
Daxx, as an H3.3-specific histone chaperone, can interact with H3.3/H4 dimers and shows its intracellular diversity through different intracellular localization and functions.
Daxx’s core functions
The role of Daxx in the nucleus is quite complex. When PML-NB is missing or disrupted, Daxx is relocalized and programmed cell death does not occur. This interaction was observed after treatment of cells in which PML-NB had been disrupted, with Daxx relocalizing to PML-NB. During the S phase of the cell cycle, Daxx colocalizes with ATRX (a component of centromeric heterochromatin).
Studies have shown that Daxx deficiency leads to dysfunction of the S phase and the formation of binucleate cells, which proves the necessity of Daxx in cell proliferation.
Daxx and apoptosis in the cytoplasm
When Fas receptors are stimulated, Daxx moves from the nucleus to the cytoplasm. This process is related to the breakdown of glucose, which generates reactive oxygen species (ROS), which in turn induces Daxx relocalization. In addition, the entry of Daxx into the cytoplasm may also depend on the CRM1 transport mechanism, which is related to phosphorylation.
The role of Daxx in apoptosis
Fas-induced apoptosis
Daxx is activated upon Fas stimulation and is involved in activating the c-JUN-N-terminal kinase (JNK) pathway, which normally regulates stress-induced cell death. It is worth noting that Daxx does not directly activate JNK, but the upstream JNK kinase ASK1.
Mechanism of TGF-β regulation
TGF-β plays an important role in a variety of cell development processes, including growth, differentiation, proliferation, and cell death. Daxx acts by binding to the C-terminus of the TGF-β type II receptor. When cells are treated with TGF-β, the nuclear kinase HIPK2 phosphorylates Daxx, thereby activating the JNK pathway and further promoting the apoptosis process.
Surprise of anti-apoptotic effect
The dual role of Daxx is surprising because it is not only involved in pro-apoptosis, but also has anti-apoptotic functions. During embryonic development, the absence or destruction of Daxx can lead to early lethality. In addition, deletion of the Daxx gene caused an increase in the apoptosis rate of embryonic stem cells, which made researchers realize the importance of Daxx in cell survival.
When Daxx combines with PML, the apoptosis rate of cells will be significantly increased, indicating that its different positions and roles in cells can affect the fate of cells.
Other features of Daxx
The systemic expression of Daxx suggests that it may function as a transcription factor. Although it contains no known DNA-binding region, Daxx can interact with and inhibit multiple transcription factors, including p53, p73, and NF-κB. In addition, Daxx can also interfere with the TGF-β pathway regulator Smad4, further expanding the scope of its biological functions.
The intersection of death and life, and the multiple roles of Daxx in this process, make us reflect on the complexity of life and the ingenious design of cellular regulation. In future research, will Daxx reveal more of the mysteries of the balance between life and death?
