Interplay between protein acetylation and ubiquitination controls MCL1 protein stability

The anti-apoptotic myeloid cell leukemia 1 (MCL1) protein belongs to the pro-survival BCL2 family and is frequently amplified or elevated in human cancers. MCL1 is highly unstable, with its stability being regulated by phosphorylation and ubiquitination. Here, we identify acetylation as another critical post-translational modification regulating MCL1 protein stability. We demonstrate that the lysine acetyltransferase p300 targets MCL1 at K40 for acetylation, which is counteracted by the deacetylase sirtuin 3 (SIRT3). Mechanistically, acetylation enhances MCL1 interaction with USP9X, resulting in deubiquitination and subsequent MCL1 stabilization. Therefore, ectopic expression of acetylation-mimetic MCL1 promotes apoptosis evasion of cancer cells, enhances colony formation potential, and facilitates xenografted tumor progression. We further demonstrate that elevated MCL1 acetylation sensitizes multiple cancer cells to pharmacological inhibition of USP9X. These findings reveal that acetylation of MCL1 is a critical post-translational modification enhancing its oncogenic function and provide a rationale for developing innovative therapeutic strategies for MCL1-dependent tumors. [Display omitted] •p300 acetylates MCL1 at K40, which is counteracted by the deacetylase SIRT3•K40 acetylation recruits USP9X, resulting in MCL1 deubiquitination and stabilization•Acetylation-mimetic MCL1 promotes evasion of apoptosis and facilitates tumorigenesis•Elevated MCL1 acetylation status sensitizes cancer cells to the USP9X inhibitor WP1130 MCL1, an anti-apoptotic BCL2 family protein, is frequently overexpressed in a variety of cancers, and its oncogenic function is finely regulated by post-translational modifications such as phosphorylation and ubiquitination. Shimizu et al. dissect the molecular mechanism of acetylation-mediated MCL1 stability control, providing insights into potential therapeutic intervention targeting the MCL1 protein.