title: The carboxyl-terminal tail of Noxa protein regulates the stability of Noxa and Mcl-1.
abstract: The BH3-only protein Noxa is a critical mediator of apoptosis and functions primarily by sequestering/inactivating the antiapoptotic Bcl-2 family protein Mcl-1. Although 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 C-terminal tail of Noxa regulates the stability of both Noxa and Mcl-1.
authors.affiliation: From the Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696.
authors.forename: Xiaming
authors.initials: X
authors.lastname: Pang
authors.affiliation: From the Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696, the Xiangya School of Medicine, Central South University, Changsha 410013, China, and.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696.
authors.forename: Hernando
authors.initials: H
authors.lastname: Lopez
authors.affiliation: From the Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696, the School of Medicine, Shandong University, Jinan 250100, China.
authors.forename: Yushu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696.
authors.forename: Wenyang
authors.initials: W
authors.lastname: Li
authors.affiliation: From the Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696.
authors.forename: Katelyn L
authors.initials: KL
authors.lastname: O'Neill
authors.affiliation: From the Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696.
authors.forename: Jacquelynn J D
authors.initials: JJ
authors.lastname: Evans
authors.affiliation: From the Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: George
authors.affiliation: the Xiangya School of Medicine, Central South University, Changsha 410013, China, and.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Long
authors.affiliation: From the Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: From the Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696, xuluo@unmc.edu.
authors.forename: Xu
authors.initials: X
authors.lastname: Luo
mesh_terms: D006367:HeLa Cells; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2
keywords: BH3-only Proteins; Bcl-2 Family Proteins; Mcl-1; Mitochondrial Apoptosis; Noxa; Protein Complex; Protein Stability; Ubiquitylation (Ubiquitination)