Interactome analysis of Bag-1 isoforms reveals novel interaction partners in endoplasmic reticulum-associated degradation.
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2021
2021
Historique:
received:
01
06
2021
accepted:
11
08
2021
entrez:
24
8
2021
pubmed:
25
8
2021
medline:
24
12
2021
Statut:
epublish
Résumé
Bag-1 is a multifunctional protein that regulates Hsp70 chaperone activity, apoptosis, and proliferation. The three major Bag-1 isoforms have different subcellular localizations and partly non-overlapping functions. To identify the detailed interaction network of each isoform, we utilized mass spectrometry-based proteomics and found that interactomes of Bag-1 isoforms contained many common proteins, with variations in their abundances. Bag-1 interactomes were enriched with proteins involved in protein processing and degradation pathways. Novel interaction partners included VCP/p97; a transitional ER ATPase, Rad23B; a shuttling factor for ubiquitinated proteins, proteasome components, and ER-resident proteins, suggesting a role for Bag-1 also in ER-associated protein degradation (ERAD). Bag-1 pull-down from cells and tissues from breast cancer patients validated these interactions and showed cancer-related prominence. Using in silico predictions we detected hotspot residues of Bag-1. Mutations of these residues caused loss of binding to protein quality control elements and impaired proteasomal activity in MCF-7 cells. Following CD147 glycosylation pattern, we showed that Bag-1 downregulated VCP/p97-dependent ERAD. Overall, our data extends the interaction map of Bag-1, and broadens its role in protein homeostasis. Targeting the interaction surfaces revealed in this study might be an effective strategy in the treatment of cancer.
Identifiants
pubmed: 34428256
doi: 10.1371/journal.pone.0256640
pii: PONE-D-21-18095
pmc: PMC8384158
doi:
Substances chimiques
BCL2-associated athanogene 1 protein
0
BSG protein, human
0
DNA-Binding Proteins
0
Protein Isoforms
0
Transcription Factors
0
Basigin
136894-56-9
Proteasome Endopeptidase Complex
EC 3.4.25.1
VCP protein, human
EC 3.6.4.6
Valosin Containing Protein
EC 3.6.4.6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0256640Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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