Noxa controls Mule-dependent Mcl-1 ubiquitination through the regulation of the Mcl-1/USP9X interaction |
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Authors: | Gomez-Bougie Patricia Ménoret Emmanuelle Juin Philippe Dousset Christelle Pellat-Deceunynck Catherine Amiot Martine |
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Affiliation: | aINSERM, UMR892, Université de Nantes, Nantes Atlantique Universités, UFR Médecine et Techniques Médicales, 44093 Nantes, France;bEquipe 10 labellisée Ligue Nationale contre le Cancer 2008, 44007 Nantes, France;cCHU de Nantes, Service d’hématologie, 44 093 Nantes, France |
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Abstract: | The level of the Mcl-1 pro-survival protein is highly regulated, and the down-regulation of Mcl-1 expression favors the apoptotic process. Mcl-1 physically interacts with different BH3-only proteins; particularly, Noxa is involved in the modulation of Mcl-1 expression. In this study, we demonstrated that Noxa triggers the degradation of Mcl-1 at the mitochondria according to the exclusive location of Noxa at this compartment. The Noxa-induced degradation of Mcl-1 required the E3 ligase Mule, which is responsible for the polyubiquitination of Mcl-1. Because the USP9X deubiquitinase was recently demonstrated to be involved in Mcl-1 protein turnover by preventing its degradation through the removal of conjugated ubiquitin, we investigated whether Noxa affected the deubiquitination process. Interestingly, Noxa over-expression caused a decrease in the USP9X/Mcl-1 interaction associated with an increase in the Mcl-1 polyubiquitinated forms. Additionally, Noxa over-expression triggered an increase in the Mule/Mcl-1 interaction in parallel with the decrease in Mule/USP9X complex formation. Taken together, these modifications result in the degradation of Mcl-1 by the proteasome machinery. The implication of Noxa in the regulation of Mcl-1 proteasomal degradation adds complexity to this process, which is governed by multiple interactions. |
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Keywords: | Noxa Mcl-1 Ubiquitination E3 ligase USP9X |
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