Chemoproteomics reveals arctigenin as a phagophore-closure blocker via targeting ESCRT-I subunit VPS28.
Bioorg Chem
; 134: 106457, 2023 05.
Article
em En
| MEDLINE
| ID: mdl-36907049
ABSTRACT
Arctigenin is the active ingredient of the traditional medicines Arctium lappa and Fructus Arctii and has been extensively investigated for its diverse pharmacological functions, including its novel anti-austerity activity. Although several mechanisms have been proposed, the direct target of arctigenin to induce anti-austerity activity remains unclear. In this study, we designed and synthesized photo-crosslinkable arctigenin probes and utilized them in the chemoproteomic profiling of potential target proteins directly in living cells. Vacuolar protein sorting-associated protein 28 (VPS28), a key subunit of the ESCRT-I complex implicated in phagophore closure, was successfully identified. Unexpectedly, we found that arctigenin degraded VPS28 via the ubiquitin-proteasome pathway. We also demonstrated that arctigenin induces a prominent phagophore closure-blockade phenotype in PANC-1 cells. To the best of our knowledge, this is the first report of a small molecule acting as a phagophore-closure blocker and a VPS28 degrader. The arctigenin-modulating phagophore closure provides a new druggable target for cancers that rely heavily on autophagy activation and may also be used for other diseases associated with the ESCRT system.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Lignanas
/
Autofagossomos
Idioma:
En
Revista:
Bioorg Chem
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China