FBXL20-mediated ubiquitination triggers the proteasomal degradation of 4-1BB.
4-1BB
FBXL20
degradation
ubiquitination
Journal
The FEBS journal
ISSN: 1742-4658
Titre abrégé: FEBS J
Pays: England
ID NLM: 101229646
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
revised:
27
12
2021
received:
23
10
2021
accepted:
01
02
2022
pubmed:
4
2
2022
medline:
5
8
2022
entrez:
3
2
2022
Statut:
ppublish
Résumé
4-1BB [tumor necrosis factor receptor superfamily (TNFRSF9), CD137) is a critical immune stimulator that sustains T cell activity and antitumor immune response. The strategy to eliminate cancers by agonistically targeting 4-1BB is under clinical investigation. As a protein expressed in an inducible manner, 4-1BB is under tight control on both transcription and translation levels to maintain its homeostasis. So far, the mechanisms underlying the transcriptional activation of 4-1BB have been well-interpreted; however, it remains inexplicit how 4-1BB is regulated on the protein level. In this study, we presented experimental evidence supporting that 4-1BB, especially the heavily N-glycosylated (mature) form, is polyubiquitinated and subjected to the ubiquitin-proteasomal system for degradation. By performing proximity-dependent biotin identification screening coupled with biochemical assays, we identified that F-box/LRR-repeat protein 20 acts as the E3 ligase that promotes the polyubiquitination of 4-1BB at the intracellular domain. Our data provided mechanistic insight into 4-1BB regulation on the protein level by unmasking, for the first time, a posttranslational mechanism governing 4-1BB abundance in cells. The findings of this study could potentially guide the development of 4-1BB-targeted therapy for cancers as well as other immune disorders.
Substances chimiques
F-Box Proteins
0
FBXL20 protein, human
0
TNFRSF9 protein, human
0
Tumor Necrosis Factor Receptor Superfamily, Member 9
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
4549-4563Informations de copyright
© 2022 Federation of European Biochemical Societies.
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