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Mitochondrial E3 ubiquitin ligase MARCHF5 controls BAK apoptotic activity independently of BH3-only proteins

Abstract

Intrinsic apoptosis is principally governed by the BCL-2 family of proteins, but some non-BCL-2 proteins are also critical to control this process. To identify novel apoptosis regulators, we performed a genome-wide CRISPR-Cas9 library screen, and it identified the mitochondrial E3 ubiquitin ligase MARCHF5/MITOL/RNF153 as an important regulator of BAK apoptotic function. Deleting MARCHF5 in diverse cell lines dependent on BAK conferred profound resistance to BH3-mimetic drugs. The loss of MARCHF5 or its E3 ubiquitin ligase activity surprisingly drove BAK to adopt an activated conformation, with resistance to BH3-mimetics afforded by the formation of inhibitory complexes with pro-survival proteins MCL-1 and BCL-XL. Importantly, these changes to BAK conformation and pro-survival association occurred independently of BH3-only proteins and influence on pro-survival proteins. This study identifies a new mechanism by which MARCHF5 regulates apoptotic cell death by restraining BAK activating conformation change and provides new insight into how cancer cells respond to BH3-mimetic drugs. These data also highlight the emerging role of ubiquitin signalling in apoptosis that may be exploited therapeutically.

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Fig. 1: Genome-wide CRISPR/Cas9 library screen identifies MARCHF5 as a regulator of BAK-dependent apoptosis.
Fig. 2: Deleting Marchf5 in combination with Vdac2 in Bax-/- MEFs impairs MOMP and cytochrome c release.
Fig. 3: MARCHF5 deletion can be sufficient to regulate BAK-dependent apoptosis.
Fig. 4: MARCHF5 deletion causes BAK activation and sequestration by pro-survival proteins.
Fig. 5: MARCHF5 regulates BAK dependent on its E3 ubiquitin ligase activity.
Fig. 6: Identification of MARCHF5 substrates that contribute to BAK activation.
Fig. 7: MARCHF5 controls BAK conformation change independently of BH3-only proteins.

Data availability

Mass spectrometry data has been deposited to the ProteomeXchange Consortium [83] via the PRIDE partner repository [84] under accession number PXD030246.

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Acknowledgements

We would like to thank Ruth Kluck, Peter Czabotar, Daniel Gray, and Andreas Strasser for helpful discussions and suggestions; Melissa Shi for technical assistance; Stephen Wilcox for DNA sequencing; Simon Cobbold for assistance with proteomic analysis; Prof Xu Luo for providing all BCL-2 genes knockout HCT116 cells; Christine White for technical support. We thank the Bio21 Mass Spectrometry and Proteomics Facility (MMSPF) for the provision of instrumentation, training, and technical support, and the Mito Foundation for the provision of instrumentation through the large equipment grant support scheme. This work was supported by scholarship fellowship and grants from the Australian National Health and Medical Research Council (NHMRC) to DAS (#1140851, #1140906); Melbourne University (MIRS and MIFRS scholarships to ASH and TMD); the Walter and Eliza Hall Institute of Medical Research (to ASH); the Bodhi Foundation and the McPhee Charitable Trust (to GD). Research was supported by an NHMRC Independent Research Institutes Infrastructure Support Scheme grant (361646) and Victorian State Government Operational Infrastructure Support grant.

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DCSH, MvD, and GD devised the study and interpreted data. ASH and HSC planned, performed experiments, and interpreted data. BR and DAS performed the proteomics and interpreted data. TMD, JNG, and IKLT generated reagents; ASH and MvD collated and analysed data. ASH, MvD, GD wrote the manuscript. All authors contributed to manuscript review.

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Correspondence to Mark F. van Delft or Grant Dewson.

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Huang, A.S., Chin, H.S., Reljic, B. et al. Mitochondrial E3 ubiquitin ligase MARCHF5 controls BAK apoptotic activity independently of BH3-only proteins. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01067-z

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