Small Molecule Modulation of Proteasome Assembly

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

Research output: Contribution to journalArticle

11 Scopus citations


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 build-up of IDPs result-ing in incorrect signaling or aggregation, associated with the pathogenesis of many cancers and neuro-degenerative diseases. Drugs that facilitate 20S-mediated proteolysis have therefore many potential therapeutic applications. We report herein the modulation of proteasome assembly by the small mole-cule TCH-165, resulting in an increase in 20S levels. The increase 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 com-plexes (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)
StateAccepted/In press - May 23 2018


ASJC Scopus subject areas

  • Biochemistry

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