Caspase control: IAPs as NEDD8 E3 ligases
A new role of inhibitor of apoptosis (IAP) proteins in caspase regulation is revealed: they can promote conjugation of the ubiquitin-like protein NEDD8 as well as ubiquitin. This adds to the complexity of IAP-mediated signaling.
Inhibitor of apoptosis (IAP) proteins act as ubiquitin E3 ligases and regulate caspase activity through ubiquitin-mediated proteasomal degradation; deubiquitylating enzymes (DUBs) can reverse the activity of ubiquitin and ubiquitin-like (UBL) proteins, such as NEDD8. In transgenic Drosophila expressing IAP antagonists to induce apoptosis, Broemer et al. have now systemically knocked down individual DUBs using RNA interference and identified three NEDD8-specific proteases that, when knocked down, suppress cell death in vivo.
Apoptosis was reduced in the null mutants of one of these genes, Deneddylase 1 (DEN1), and the effector caspase drICE was found to be neddylated in vivo, which suggested a role for NEDD8 in apoptosis. Interestingly, UV mediated reduction in Drosophila IAP 1 (DIAP1) protein levels reduced neddylation of drICE and induced apoptosis, indicating that DIAP1 is a NEDD8 E3 ligase for drICE.
Further investigation showed that DIAP1 neddylates drICE in a RING- and binding-dependent manner leading to reduced drICE proteolytic activity, and further mass spectrometry analysis identified nine lysine residues in drICE as sites for neddylation.
As XIAP, a mammalian IAP, also promoted neddylation of caspase 7 in a RING-dependent manner, IAP-mediated neddylation seems to be evolutionarily conserved.
This study demonstrates that IAPs can function as E3 ligases for NEDD8 as well as for ubiquitin and extends the complexity of IAP-mediated signaling.
Iley Ozerlat
Signaling Gateway
Reference:
Broemer M. et al.
Systematic in vivo RNAi analysis identifies IAPs as NEDD8-E3 ligases.
Mol. Cell 40, 810-812 (2010)
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