The intrinsic apoptosis pathway is mediated by Bcl-2 family proteins, such as Bax. Kornbluth and colleagues now identify a link between the anaphase-promoting complex/cyclosome (APC/C) and apoptosis by demonstrating that the modulator of apoptosis protein (MOAP-1), an enhancer of Bax function, is stabilized through Trim39-mediated inhibition of APC/C (J. Cell Biol. 197, 361–367; 2012).
The authors identify Trim39 as a human homologue of Xnf7, a Xenopus laevis E3 ligase that they previously found to inhibit the APC/C. They also demonstrate that Trim39 inhibits ubiquitylation of the APC/C substrate cyclin B1, indicating that this role may be conserved. MOAP-1 was previously shown to be stabilized by Trim39; this is confirmed by the current study, which shows that MOAP-1 is degraded in the G1 phase of the cell cycle. Further, the authors find that MOAP-1 is a target of the APC/C cofactor Cdh1, as mutation of D-box sequences stabilizes the protein, whereas Cdh1 overexpression promotes its ubiquitylation. In accordance with MOAP-1 being a target of APC/C–Cdh1, chemotherapy-induced activation of Bax and apoptosis is enhanced by Cdh1 depletion, in a manner at least partly dependent on MOAP-1. How the APC/C is inhibited by Trim39 remains unclear, but the mechanism may involve ubiquitylation of an APC/C regulator, as the catalytic activity of Trim39 is required. More work will also be needed to elucidate how MOAP-1 degradation could help coordinate apoptosis with the cell cycle.
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Rosenthal, C. Trim39 ligase keeps apoptosis going. Nat Cell Biol 14, 566 (2012). https://doi.org/10.1038/ncb2516
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DOI: https://doi.org/10.1038/ncb2516