Ubiquitin-Independent Degradation of Antiapoptotic MCL-1

Abstract

Antiapoptotic myeloid cell leukemia 1 (MCL-1) is an essential modulator of survival during the development and maintenance of a variety of cell lineages. Its turnover, believed to be mediated by the ubiquitin-proteasome system, facilitates apoptosis induction in response to cellular stress. To investigate the contribution of ubiquitinylation in regulating murine MCL-1 turnover, we generated an MCL-1 mutant lacking the lysine residues required for ubiquitinylation (MCL-1^KR). Here, we demonstrate that despite failing to be ubiquitinylated, the MCL-1^KR protein is eliminated at a rate similar to that of wild-type MCL-1 under basal and stressed conditions. Moreover, the degradation of wild-type MCL-1 is not affected when ubiquitin-activating enzyme E1 activity is blocked. Likewise, both wild-type and MCL-1^KR proteins are similarly degraded when expressed in primary lymphocytes. Supporting these findings, unmodified, in vitro-translated MCL-1 can be degraded in a cell-free system by the 20S proteasome. Taken together, these data demonstrate that MCL-1 degradation can occur independently of ubiquitinylation.

View publisher note:

Articles of Significant Interest Selected from This Issue by the Editors

We thank S. Oakes, L. Nutt, D. Green, J. Ihle, G. Zambetti, J. Partridge, P. Brindle, and P. Ney for helpful discussions; the St. Jude Transgenic Core Facility for generating the transgenic mice; and J. Roberts, H. Ozer, D. Bohman, K. Helin, M. Pagano, C. Sherr, D. Green, and J. W. Harper for providing reagents.

This work is supported by the American Lebanese Syrian Associated Charities (ALSAC), and the NIH NCI P30CA021765-30. J.T.O. is a Pew Scholar in the Biomedical Sciences.