Mcl-1 Ubiquitination: Unique Regulation of an Essential Survival Protein

Barbara Mojsa (1) , Irena Lassot (1) , Solange Desagher (1)

1 IGMM - Institut de Génétique Moléculaire de Montpellier

Mcl-1 is an anti-apoptotic protein of the Bcl-2 family that is essential for the survival of multiple cell lineages and that is highly amplified in human cancer. Under physiological conditions, Mcl-1 expression is tightly regulated at multiple levels, involving transcriptional, post-transcriptional and post-translational processes. Ubiquitination of Mcl-1, that targets it for proteasomal degradation, allows for rapid elimination of the protein and triggering of cell death, in response to various cellular events. In the last decade, a number of studies have elucidated different pathways controlling Mcl-1 ubiquitination and degradation. Four different E3 ubiquitin-ligases (e.g., Mule, SCF β-TrCP , SCF Fbw7 and Trim17) and one deubiquitinase (e.g., USP9X), that respectively mediate and oppose Mcl-1 ubiquitination, have been formerly identified. The interaction between Mule and Mcl-1 can be modulated by other Bcl-2 family proteins, while recognition of Mcl-1 by the other E3 ubiquitin-ligases and deubiquitinase is influenced by phosphorylation of specific residues in Mcl-1. The protein kinases and E3 ubiquitin-ligases that are involved in the regulation of Mcl-1 stability vary depending on the cellular context, highlighting the complexity and pivotal role of Mcl-1 regulation. In this review, we attempt to recapitulate progress in understanding Mcl-1 regulation by the ubiquitin-proteasome system.

Mots clés: Mcl-1; ubiquitin; proteasome; apoptosis; phosphorylation; E3 ubiquitin-ligase; deubiquitinase

Domaines: Biologie cellulaire

Barbara Mojsa, Irena Lassot, Solange Desagher. Mcl-1 Ubiquitination: Unique Regulation of an Essential Survival Protein. Cells, 2014, 3 (2), pp.418-437. ⟨10.3390/cells3020418⟩. ⟨hal-02108525⟩