FBXL20‐mediated ubiquitination triggers the proteasomal degradation of 4‐1BB

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...

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Bibliographic Details
Published in:The FEBS journal 2022-08, Vol.289 (15), p.4549-4563
Main Authors: Sun, Ruoxuan, Lim, Seung‐Oe
Format: Article
Language:English
Subjects:
4‐1BB
Anticancer properties
Antitumor activity
Biotin
Cancer
CD137 antigen
Degradation
FBXL20
Homeostasis
Immune response
Immune system
Lymphocytes
Lymphocytes T
Proteasomes
Proteins
Stimulators
Transcription activation
Ubiquitin
Ubiquitin-protein ligase
Ubiquitination
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Summary: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. 4‐1BB is a critical immune stimulator that sustains T cell activity and antitumor immune response. In this study, we present experimental evidence supporting that 4‐1BB is polyubiquitinated and subjected to the ubiquitin‐proteasomal system for degradation. Proteomics analysis identified that F‐box/LRR‐repeat protein 20 serves as one of the E3 ligases to ubiquitinate and destabilize 4‐1BB. Our findings could guide the development of 4‐1BB‐targeted therapy for cancer as well as other immune disorders.
ISSN:1742-464X
1742-4658
DOI:10.1111/febs.16383