Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 49, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2117254118
Keywords
ubiquitin-proteasome; KPC1; NF-kappa B; p50; PROTAC
Categories
Funding
- Adelson Medical Research Foundation
- Israel Science Foundation
- Albert Sweet Foun-dation
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NF-kappa B is a crucial transcriptional regulator that relies on the UPS for activation and employs the ubiquitin ligase KPC1 for ubiquitination of p105 to generate p50, suppressing tumor growth. By linking the short amino acid sequence WILVRLW to the ligase, it can effectively bind p105 and limit cell growth.
Nuclear factor kappa B (NF-kappa B) is an important transcriptional regulator that is involved in numerous cellular processes, including cell proliferation, immune response, cell survival, and malignant transformation. It relies on the ubiquitin-proteasome system (UPS) for several of the steps in the concerted cascade of its activation. Previously, we showed that the ubiquitin (Ub) ligase KPC1 is involved in ubiquitination and limited proteasomal processing of the NF-kappa B1 p105 precursor to generate the p50 active subunit of the canonical heterodimeric transcription factor p50-p65. Overexpression of KPC1 with the generation of an excessive amount of p50 was shown to suppress tumors, an effect which is due to multiple mechanisms. Among them are suppression of expression of programmed cell death-ligand 1 (PD-L1), overexpression of a broad array of tumor suppressors, and secretion of cytokines which results in recruitment of suppressive immune cells into the tumor. Here, we show that the site of KPC1 to which p105 binds is exceptionally short and is made up of the seven amino acids WILVRLW. Attachment of this short stretch to a small residual part (similar to 20%) of the ligase that also contains the essential Really Interesting New Gene (RING)-finger domain was sufficient to bind p105, conjugate to it Ub, and suppress tumor growth in an animal model. Fusion of the seven amino acids to a Von Hippel-Lindau protein (pVHL)-binding ligand (which serves as a universal ligase for many proteolysis-targeting chimeras; PROTACs) resulted in a compound that stimulated conjugation of Ub to p105 in a cell-free system and its processing to p50 in cells and restricted cell growth.
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