PXD030246-1

PXD030246 is an original dataset announced via ProteomeXchange.

Title	Mitochondrial E3 ubiquitin ligase MARCHF5 controls BAK function independently of BH3-only proteins
Description	Intrinsic apoptosis is principally regulated by the BCL-2 family of proteins, but some non-BCL-2 proteins also serve as important regulators. 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 multiple BAX-deficient cell lines conferred profound resistance to BH3-mimetic drugs. The loss of MARCHF5 or its E3 ubiquitin ligase activity surprisingly drove BAK to adopt an active 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. This study identifies a 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.
HostingRepository	PRIDE
AnnounceDate	2022-09-26
AnnouncementXML	Submission_2022-09-25_16:07:19.485.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	David Stroud
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2021-12-08 07:57:16	ID requested
⏵ 1	2022-09-25 16:07:19	announced
2	2023-11-14 08:53:56	announced	2023-11-14: Updated project metadata.

10.1038/S41418-022-01067-Z;

submitter keyword: Apoptosis

BAK

BCL-2

MARCHF5/MITOL

E3 ubiquitin ligase

mitochondria

BH3 mimetic

David Stroud
contact affiliation	Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia
contact email	david.stroud@unimelb.edu.au
lab head
David Stroud
contact affiliation	The University of Melbourne
contact email	david.stroud@unimelb.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD030246
     1. Label: PRIDE project
     2. Name: Mitochondrial E3 ubiquitin ligase MARCHF5 controls BAK function independently of BH3-only proteins