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Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity.

ABSTRACT: The endoplasmic reticulum (ER) is responsible for folding secretory and membrane proteins, but disturbed ER proteostasis may lead to protein aggregation and subsequent cellular and clinical pathologies. Chemical chaperones have recently emerged as a potential therapeutic approach for ER stress-related diseases. Here, we identified 2-phenylimidazo[2,1-b]benzothiazole derivatives (IBTs) as chemical chaperones in a cell-based high-throughput screen. Biochemical and chemical biology approaches revealed that IBT21 directly binds to unfolded or misfolded proteins and inhibits protein aggregation. Finally, IBT21 prevented cell death caused by chemically induced ER stress and by a proteotoxin, an aggression-prone prion protein. Taken together, our data show the promise of IBTs as potent chemical chaperones that can ameliorate diseases resulting from protein aggregation under ER stress.

SUBMITTER: Kitakaze K

PROVIDER: S-EPMC6922633 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity.

Kitakaze Keisuke K Taniuchi Shusuke S Kawano Eri E Hamada Yoshimasa Y Miyake Masato M Oyadomari Miho M Kojima Hirotatsu H Kosako Hidetaka H Kuribara Tomoko T Yoshida Suguru S Hosoya Takamitsu T Oyadomari Seiichi S

eLife 20191217

The endoplasmic reticulum (ER) is responsible for folding secretory and membrane proteins, but disturbed ER proteostasis may lead to protein aggregation and subsequent cellular and clinical pathologies. Chemical chaperones have recently emerged as a potential therapeutic approach for ER stress-related diseases. Here, we identified 2-phenylimidazo[2,1-<i>b</i>]benzothiazole derivatives (IBTs) as chemical chaperones in a cell-based high-throughput screen. Biochemical and chemical biology approache ...[more]

PMID: 31843052

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Project description:Peptidoglycan (PG) is the main structural component of bacterial envelopes. It protects bacterial cells against variations in osmotic pressure and cell lysis. The newly discovered Escherichia coli factor ElyC has been shown to be important for peptidoglycan biosynthesis at low temperatures. PG production in ?elyC mutant cells is totally blocked after a few hours of growth at 21°C, triggering cell lysis. In this study, we took a candidate approach to identify genetic suppressors of the ?elyC mutant cell lysis phenotype. We identified the periplasmic proteins DsbG and Spy as multicopy suppressors and showed that their overproduction restores PG biosynthesis in the ?elyC mutant. Interestingly, we found that DsbG acts by a novel mechanism, which is independent of its known reductase activity and substrates. DsbG, like Spy, acts as a chaperone to reduce the amounts of protein aggregates in the envelopes of ?elyC cells. In fact, we found that the amount of protein aggregates was greater in the ?elyC mutant than in the wild type. Taken together, our results show a protein-folding defect in the envelope compartments of ?elyC cells that blocks PG production, and they reveal a new physiological activity of DsbG.IMPORTANCE Peptidoglycan biosynthesis is a dynamic and well-controlled pathway. The molecular assembly of PG and the regulatory pathways ensuring its maintenance are still not well understood. Here we studied the newly discovered Escherichia coli factor ElyC, which is important for PG biosynthesis at low temperatures. We revealed an important protein-folding defect in the ?elyC mutant and showed that overproduction of the periplasmic chaperone DsbG or Spy was sufficient to correct the protein-folding defect and restore PG biosynthesis. These results show that the PG defect in the absence of ElyC is caused, at least in part, by a protein-folding problem in the cell envelope. Furthermore, we showed, for the first time, that the periplasmic protein DsbG has chaperone activity in vivo.

Dataset Information

Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity.

Publications

Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity.

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