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

AS Huang; HS Chin; B Reljic; TM Djajawi; IKL Tan; JN Gong; DA Stroud; DCS Huang; MF van Delft; G Dewson

Journal article

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

AS Huang, HS Chin, B Reljic, TM Djajawi, IKL Tan, JN Gong, DA Stroud, DCS Huang, MF van Delft, G Dewson

Cell Death and Differentiation | Published : 2023

DOI: 10.1038/s41418-022-01067-z

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 prot..

View full abstract

University of Melbourne Researchers

David Stroud Author

David Huang Author

Mark van Delft Author

Grant Dewson Author

Related Projects (2)

SYSTEMS APPROACHES TO UNDERSTANDING MITOCHONDRIAL FUNCTION AND DYSFUNCTION IN DISEASE

Mitochondria produce the energy for our bodies. Defects in this process cause mitochondrial disease, which affects at least 1/4300 people. D..

SYSTEMS APPROACHES TO UNDERSTANDING THE ASSEMBLY OF MITOCHONDRIAL MACHINES

Mitochondria produce the energy for our bodies. Defects in this process cause mitochondrial disease, which affects at least 1/5000 people. D..

Grants

Awarded by National Health and Medical Research Council

Funding 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.