Small Molecule Modulation of Proteasome Assembly

Evert Njomen, Pawel A. Osmulski, Corey L. Jones, Maria Gaczynska, Jetze J. Tepe

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

The 20S proteasome is the main protease that directly targets intrinsically disordered proteins (IDPs) for proteolytic degradation. Mutations, oxidative stress, or aging can induce the buildup of IDPs resulting in incorrect signaling or aggregation, associated with the pathogenesis of many cancers and neurodegenerative diseases. Drugs that facilitate 20S-mediated proteolysis therefore have many potential therapeutic applications. We report herein the modulation of proteasome assembly by the small molecule TCH-165, resulting in an increase in 20S levels. The increase in the level of free 20S corresponds to enhanced proteolysis of IDPs, including α-synuclein, tau, ornithine decarboxylase, and c-Fos, but not structured proteins. Clearance of ubiquitinated protein was largely maintained by single capped proteasome complexes (19S-20S), but accumulation occurs when all 19S capped proteasome complexes are depleted. This study illustrates the first example of a small molecule capable of targeting disordered proteins for degradation by regulating the dynamic equilibrium between different proteasome complexes.

Original languageEnglish (US)
Pages (from-to)4214-4224
Number of pages11
JournalBiochemistry
Volume57
Issue number28
DOIs
StatePublished - Jul 17 2018

ASJC Scopus subject areas

  • Biochemistry

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