The Carboxyl-terminal Tail of Noxa Regulates the Stability of Noxa and Mcl-1 [Protein Synthesis and Degradation]

May 8th, 2014 by Pang, X., Zhang, J., Lopez, H., Wang, Y., Li, W., O'Neil, K. L., Evans, J. J. D., George, N. M., Long, J., Chen, Y., Luo, X.

The BH3-only protein Noxa is a critical mediator of apoptosis, and functions primarily by sequestering/inactivating the anti-apoptotic Bcl-2 family protein Mcl-1. While Noxa is a highly labile protein, recent studies suggested that it is degraded by the proteasome in a ubiquitylation-independent manner. In the present study, we investigated the mechanism of Noxa degradation and its ability to regulate the stability of Mcl-1. We found that the ubiquitylation-independent degradation of Noxa does not require a physical association with Mcl-1. A short stretch of amino acid residues in the C-terminal tail was found to mediate the proteasome-dependent degradation of Noxa. Ectopic placement of this degron was able to render other proteins unstable. Surprisingly, mutation of this sequence not only attenuated the rapid degradation of Noxa, but also stabilized endogenous Mcl-1 through the BH3-mediated direct interaction. Together, these results suggest that the Carboxyl-terminal tail of Noxa regulates the stability of both Noxa and Mcl-1.