Related Experiment Video

Updated: Aug 27, 2025

Examining BCL-2 Family Function with Large Unilamellar Vesicles
08:35

Examining BCL-2 Family Function with Large Unilamellar Vesicles

Published on: October 5, 2012

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

Allan Shuai Huang1,2, Hui San Chin1,2, Boris Reljic3,4

  • 1Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Melbourne, VIC, 3052, Australia.

Cell Death and Differentiation
|September 28, 2022
PubMed

Insights

Researchers discovered MARCHF5 regulates programmed cell death by controlling BAK protein conformation. Loss of MARCHF5 activates BAK, conferring resistance to cancer drugs, revealing a new apoptosis pathway.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Intrinsic apoptosis is primarily regulated by BCL-2 family proteins.
  • Non-BCL-2 proteins also play crucial roles in controlling apoptosis.

Purpose of the Study:

  • To identify novel regulators of apoptosis.
  • To investigate the role of MARCHF5 in regulating BAK apoptotic function.

Main Methods:

  • Genome-wide CRISPR-Cas9 library screen.
  • Deletion of MARCHF5 in BAK-dependent cell lines.
  • Analysis of BAK conformation and protein interactions.

Main Results:

  • MARCHF5 (RNF153) was identified as a regulator of BAK.
  • MARCHF5 deletion or loss of its ligase activity activates BAK.
  • Activated BAK forms inhibitory complexes with MCL-1 and BCL-XL, conferring resistance to BH3-mimetics.
  • These changes occur independently of BH3-only proteins.

Conclusions:

  • MARCHF5 restrains BAK activation, thus regulating apoptotic cell death.
  • This study reveals a novel mechanism of apoptosis regulation involving ubiquitin signaling.
  • Findings offer insights into cancer cell resistance to BH3-mimetic drugs and potential therapeutic targets.

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