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bioRxiv · 10.1101/2022.01.04.474880

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

Dewson, G.·Huang, A. S.·Chin, H. S.·Reljic, B.·Djajawi, T. M.·Tan, I. K.·Stroud, D. A.·Huang, D. C. S.·van Delft, M. F.
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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 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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Dewson, G., Huang, A. S., Chin, H. S., Reljic, B., Djajawi, T. M., Tan, I. K., Stroud, D. A., Huang, D. C. S., van Delft, M. F.. 2022-01-04. E3 ubiquitin ligase MARCHF5 controls BAK apoptotic activity independently of BH3-only proteins. https://doi.org/10.1101/2022.01.04.474880

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