Trends in Cell Biology
Daxx: death or survival protein?
Introduction
Apoptosis is a genetically controlled process for the elimination of the cell in which it occurs. In certain types of rapid apoptosis such as death receptor-induced apoptosis, the apoptotic machinery is activated in the absence of de novo protein synthesis and mainly involves cytoplasmic regulators. By contrast, other types of apoptosis require de novo protein synthesis. For instance, certain apoptotic stimuli can activate transcription factors that, in turn, regulate the expression of apoptosis regulators, thus altering the balance between pro- and anti-apoptotic players present in the cell. Apoptosis is, therefore, often the result of a combination of cytoplasmic and nuclear events.
The death-domain-associated protein (Daxx) could be associated with both nuclear and cytoplasmic events during apoptosis. Daxx was originally identified as a protein that specifically binds to the death domain of the transmembrane death receptor FAS (also called CD95) in the cytoplasm and potentiates FAS-induced apoptosis [1]. A large proportion of Daxx molecules are nuclear, however, and associate with the promyelocytic leukaemia (PML) nuclear body (PML-NB) and other subnuclear domains. As Pml is required for FAS-induced cell death and Daxx pro-apoptotic function 2, 3, it has been proposed that the two proteins might participate in a nuclear pathway for apoptosis. Here, we evaluate critically the current understanding of the role of Daxx in cell death and propose new avenues for investigation.
Section snippets
Daxx structure, cellular localization and interacting partners
Daxx is a poorly characterized protein at the structural level. Among the putative domains, it contains two N-terminal paired amphipathic helices (PAHs), similar to those found in corepressors such as Sin3A; a coiled-coil domain; an acidic region; and a C-terminal serine/proline/threonine rich region (Figure 1a). Daxx is ubiquitously expressed throughout the body with particular high expression in the thymus and testes [1]. At the cellular level, Daxx is mainly a nuclear protein that associates
Daxx in FAS-induced apoptosis
Daxx interacts with pro-apoptotic receptors such as FAS and TGFβ receptor II 1, 15. The canonical FAS pathway for apoptosis is based on the recruitment of the FAS-associated death domain (FADD) protein, which, in turn, activates caspase-8 and downstream caspases. Daxx has been suggested to function as a pro-apoptotic protein downstream of FAS through activation of the c-Jun-N-terminal kinase (JNK) pathway in a FADD-independent manner 1, 16. The JNK pathway regulates stress-induced cell death
Anti-apoptotic function of Daxx
Despite the reports advocating a pro-cell-death function for Daxx, several studies have suggested a potential anti-apoptotic function for Daxx. In the embryo, Daxx appears to be anti-apoptotic and its expression appears to be important for embryonic development because disruption of the Daxx gene in the mouse results in early embryonic lethality (E9.5), with extensive apoptosis evident in Daxx−/− embryos by E7.5 [28]. Furthermore, in Daxx−/− embryonic stem (ES) cells, higher levels of
Role of Daxx in caspase-independent cell death
So far, we have highlighted works concerning Daxx function in apoptotic caspase-dependent types of cell death. A few reports suggest, however, a role for Daxx in caspase-independent cell death. This is of particular interest in view of the involvement of JNK in caspase-independent and non-apoptotic types of cell death, such as necrosis and autophagy 33, 34.
Gongora et al. [35] demonstrated that IFNα/β triggers a caspase-independent type of cell death in B-cell precursors and induces the
The role of Daxx in transcriptional regulation
On the basis that Daxx is localized to the nucleus, several groups have attempted to define its potential transcriptional functions. Although Daxx apparently does not contain any canonical DNA binding domain, the presence of two amphipathic helices with a degree of homology to co-repressors suggests that it bears co-repressive functions [42]. Indeed, Daxx is known to repress several transcription factors, including Pax3 [42], ETS1 [43], E2F1 [30], NF-κB [30], p53 44, 45 and p73 [44]. Moreover,
Concluding remarks
Several studies have attempted to determine the precise function of Daxx in cell death, and their findings indicate that it can bear both pro- and anti-cell-death activities depending on the stimulus and the cell type. Nevertheless, it appears that in primary cells Daxx acts as a death protein by regulating stress kinases such as JNK and p38. The main future task will be to identify the precise mechanisms by which Daxx exerts its functions. There are several outstanding questions:
- (i)
How does Daxx
Acknowledgements
We thank Pierluigi Nicotera, Gerry Cohen and Miguel Martins (MRC Leicester) for critical reading of the article and scientific discussion.
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