Journal
FEBS JOURNAL
Volume 289, Issue 15, Pages 4549-4563Publisher
WILEY
DOI: 10.1111/febs.16383
Keywords
4-1BB; degradation; FBXL20; ubiquitination
Categories
Funding
- Susan G. Komen Breast Cancer Foundation [CCR17488088]
- Ralph W. and Grace M. Showalter Research Trust
- Purdue Institute for Drug Discovery (PIDD) Programmatic Area grant
- Purdue Center for Cancer Research
- NIH
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This study reveals a novel mechanism for the regulation of 4-1BB at the protein level, involving polyubiquitination and degradation via the ubiquitin-proteasomal system. These findings may provide guidance for the development of targeted therapies for cancer and other immune disorders.
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.
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