PXD042004

PXD042004 is an original dataset announced via ProteomeXchange.

Title	TRIM21 enhances bortezomib sensitivity in multiple myeloma by halting pro-survival autophagy
Description	Bortezomib (bort) is an effective therapeutic agent for multiple myeloma (MM) patients; however, the majority of patients develop drug resistance. Autophagy, a highly conserved process that recycles cytosol or entire organelles via lysosomal activity, is essential for the survival, homeostasis and drug resistance in MM. Growing evidence has highlighted that E3 ligase tripartite motif-containing protein 21 (TRIM21) not only interacts with multiple autophagy regulators but also participates in drug resistance in various cancers. However, to date, the direct substrates and additional roles of TRIM21 in MM remain unexplored. In this study, we demonstrated that low TRIM21 expression is a factor for relapse in MM. TRIM21 knockdown (KD) made MM cells more resistant to bort, while TRIM21 overexpression (OE) resulted in increased MM sensitivity to bort. Proteomic and phospho-proteomic studies of TRIM21 KD MM cells showed that bort resistance was associated with increased oxidative stress and elevated pro-survival autophagy. Our results provided that TRIM21 KD MM cell lines induced pro-survival autophagy after bort treatment, and suppressing autophagy by 3-methyladenine treatment or by the short hairpin RNA of ATG5 restored bort sensitivity. Indeed, autophagy-related gene 5 (ATG5) expression was increased and decreased by TRIM21 KD and OE, respectively. TRIM21 affected autophagy by ubiquitinating ATG5 through K48 for proteasomal degradation. Importantly, we confirmed that TRIM21 could potentiate the anti-myeloma effect of bort through in vitro and in vivo experiments. Overall, our findings define the key role of TRIM21 in MM bort resistance and provide a foundation for a novel targeted therapeutic approaches.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:09:33.093.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jing Chen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	ubiquitinylated lysine
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2023-05-05 01:13:59	ID requested
1	2023-10-24 12:38:10	announced
⏵ 2	2023-11-14 09:09:41	announced	2023-11-14: Updated project metadata.

Chen J, Cao W, Huang X, Chen Q, Ye S, Qu J, Liu Y, Guo X, Yao S, Zhang E, He J, Li A, Yang L, Cai Z, TRIM21 enhances bortezomib sensitivity in multiple myeloma by halting prosurvival autophagy. Blood Adv, 7(19):5752-5770(2023) [pubmed]

submitter keyword: TRIM21;multiple myeloma;bortezomib

Jing Chen
contact affiliation	Bone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
contact email	11418106@zju.edu.cn
lab head
Jing Chen
contact affiliation	Bone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine
contact email	11418106@zju.edu.cn
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/10/PXD042004

PRIDE project URI

• PRIDE
  1. PXD042004
     1. Label: PRIDE project
     2. Name: TRIM21 enhances bortezomib sensitivity in multiple myeloma by halting pro-survival autophagy