Interplay between protein acetylation and ubiquitination controls MCL1 protein stability

Shimizu, Kouhei; Gi, Min; Suzuki, Shugo; North, Brian J.; Watahiki, Asami; Fukumoto, Satoshi; Asara, John M.; Tokunaga, Fuminori; Wei, Wenyi; Inuzuka, Hiroyuki

doi:10.1016/j.celrep.2021.109988

“…ACLY may thus additionally regulate BCL-2 levels on a post-translational level favoring its acetylation. In line with this scenario, acetyl-CoA was shown to regulate apoptotic sensitivity by promoting BCL-xL N-alpha-acetylation 32 and an interplay between protein acetylation and ubiquitination has been recently shown to control the stability of the anti-apoptotic protein MCL-1 33 . Whereas further studies will be necessary to fully dissect how exactly ACLY couples PTEN loss and BCL-2 up-regulation to promote apoptosis resistance, our data pointing out a role for ACLY in glucocorticoid-induced apoptosis resistance are intriguing as PI3K/PTEN alterations are associated with glucocorticoid resistance in clinical settings 5, 8, 11 .…”

Section: Discussionmentioning

confidence: 82%

ATP citrate lyase is an essential player of the metabolic rewiring induced by PTEN loss during T-ALL development

Andrieu

¹

,

Hypolite

²

,

Balducci

³

et al. 2023

Preprint

0

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Alterations inactivating the tumor suppressor gene PTEN drive the development of solid and hematological cancers, such as T-cell acute lymphoblastic leukemia (T- ALL), whereby PTEN loss defines poor-prognosis patients. We investigated the metabolic rewiring induced by PTEN loss in T-ALL, aiming at identifying novel metabolic vulnerabilities. We showed that the enzyme ATP citrate lyase (ACLY) is strictly required for the transformation of thymic immature progenitors and for the growth of human T-ALL, which remain dependent on ACLY activity even upon transformation. Whereas PTEN mutant mice all died within 17 weeks, the concomitant ACLY deletion prevented disease initiation in 70% of the animals, where it prevented the apoptosis of pre-malignant DP thymocytes by up-regulating BCL-2. Transcriptomic and metabolic analysis of primary T-ALL cells next translated our findings to the human pathology, showing that PTEN-altered T-ALL cells selectively activate ACLY and are specifically sensitive to its genetic targeting. ACLY activation thus represents a metabolic vulnerability with therapeutic potential for high-risk T-ALL patients.

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“…The match between simulation and experiment in both lines was improved by decreasing the abundance of MCL1. Biologically, this could be mediated by the truncated p300 expressed in RC-K8 cells, which reduces the acetylation of MCL1 thereby decreasing MCL1 protein stability 38 . In SUDHL8 cells, mutated TP53 may cause the reduced gene expression of MCL1 (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Computational modeling of DLBCL predicts response to BH3-mimetics

Cloete

¹

,

Smith

²

,

Jackson

³

et al. 2023

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In healthy cells, pro- and anti-apoptotic BCL2 family and BH3-only proteins are expressed in a delicate equilibrium. In contrast, this homeostasis is frequently perturbed in cancer cells due to the overexpression of anti-apoptotic BCL2 family proteins. Variability in the expression and sequestration of these proteins in Diffuse Large B cell Lymphoma (DLBCL) likely contributes to variability in response to BH3-mimetics. Successful deployment of BH3-mimetics in DLBCL requires reliable predictions of which lymphoma cells will respond. Here we show that a computational systems biology approach enables accurate prediction of the sensitivity of DLBCL cells to BH3-mimetics. We found that fractional killing of DLBCL, can be explained by cell-to-cell variability in the molecular abundances of signaling proteins. Importantly, by combining protein interaction data with a knowledge of genetic lesions in DLBCL cells, our in silico models accurately predict in vitro response to BH3-mimetics. Furthermore, through virtual DLBCL cells we predict synergistic combinations of BH3-mimetics, which we then experimentally validated. These results show that computational systems biology models of apoptotic signaling, when constrained by experimental data, can facilitate the rational assignment of efficacious targeted inhibitors in B cell malignancies, paving the way for development of more personalized approaches to treatment.

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“…The match between simulation and experiment in both lines was improved by decreasing the abundance of MCL1. Biologically, this could be mediated by the truncated p300 expressed in RC-K8 cells, which reduces the acetylation of MCL1 thereby decreasing MCL1 protein 41 In SUDHL8 cells, mutated TP53 may cause the reduced gene expression of MCL1 (Figure S4A and B). 42 While the simulation accurately predicted the response of SUDHL10 and U2946 cells to the MCL1 inhibitor S63845, the simulation only predicted apoptosis at high doses of the inhibitor (Figure 3).…”

Section: Considering Genetic Lesions In Virtual Lymphoma Can Improve ...mentioning

confidence: 99%

Computational modeling of DLBCL predicts response to BH3-mimetics

Cloete

¹

,

Smith

²

,

Jackson

³

et al. 2023

Preprint

View full text Add to dashboard Cite

In healthy cells, pro- and anti-apoptotic BCL2 family and BH3-only proteins are expressed in a delicate equilibrium. In contrast, this homeostasis is frequently perturbed in cancer cells due to the overexpression of anti-apoptotic BCL2 family proteins. Variability in the expression and sequestration of these proteins in Diffuse Large B cell Lymphoma (DLBCL) likely contributes to variability in response to BH3-mimetics. Successful deployment of BH3-mimetics in DLBCL requires reliable predictions of which lymphoma cells will respond. Here we show that a computational systems biology approach enables accurate prediction of the sensitivity of DLBCL cells to BH3-mimetics. We found that fractional killing of DLBCL, can be explained by cell-to-cell variability in the molecular abundances of signaling proteins. Importantly, by combining protein interaction data with a knowledge of genetic lesions in DLBCL cells, our in silico models accurately predict in vitro response to BH3-mimetics. Furthermore, through virtual DLBCL cells we predict synergistic combinations of BH3-mimetics, which we then experimentally validated. These results show that computational systems biology models of apoptotic signaling, when constrained by experimental data, can facilitate the rational assignment of efficacious targeted inhibitors in B cell malignancies, paving the way for development of more personalized approaches to treatment.

show abstract

Interplay between protein acetylation and ubiquitination controls MCL1 protein stability

Cited by 28 publications

References 63 publications

ATP citrate lyase is an essential player of the metabolic rewiring induced by PTEN loss during T-ALL development

ATP citrate lyase is an essential player of the metabolic rewiring induced by PTEN loss during T-ALL development

Computational modeling of DLBCL predicts response to BH3-mimetics

Computational modeling of DLBCL predicts response to BH3-mimetics

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