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Identification of a...
Identification of a novel compound that simultaneously impairs the ubiquitin-proteasome system and autophagy
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- Giovannucci, Tatiana A. (författare)
- Karolinska Institutet
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- Salomons, Florian A. (författare)
- Karolinska Institutet
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- Stoy, Henriette (författare)
- Department of Cell and Molecular Biology (CMB), Karolinska Institutet, Stockholm, Sweden
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- Herzog, Laura K. (författare)
- Department of Cell and Molecular Biology (CMB), Karolinska Institutet, Stockholm, Sweden
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- Xu, Shanshan (författare)
- Department of Cell and Molecular Biology (CMB), Karolinska Institutet, Stockholm, Sweden
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- Qian, Weixing (författare)
- Umeå universitet,Kemiska institutionen
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- Merino, Lara G. (författare)
- Karolinska Institutet
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- Gierisch, Maria E. (författare)
- Karolinska Institutet
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- Haraldsson, Martin (författare)
- Karolinska Institutet
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- Lystad, Alf H. (författare)
- Department of Molecular Medicine, Institute of Basic Medical Sciences and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Blindern, Oslo, Norway
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- Uvell, Hanna (författare)
- Umeå universitet,Kemiska institutionen
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- Simonsen, Anne (författare)
- Department of Molecular Medicine, Institute of Basic Medical Sciences and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Blindern, Oslo, Norway; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Montebello, Norway
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- Gustavsson, Anna-Lena (författare)
- Karolinska Institutet
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- Vallin, Michaela (författare)
- Karolinska Institutet
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- Dantuma, Nico P. (författare)
- Karolinska Institutet
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(creator_code:org_t)
- 2021-11-05
- 2022
- Engelska.
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Ingår i: Autophagy. - : Taylor & Francis. - 1554-8627 .- 1554-8635. ; 18:7, s. 1486-1502
- Relaterad länk:
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https://doi.org/10.1...
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https://umu.diva-por... (primary) (Raw object)
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https://www.tandfonl...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- The ubiquitin-proteasome system (UPS) and macroautophagy/autophagy are the main proteolytic systems in eukaryotic cells for preserving protein homeostasis, i.e., proteostasis. By facilitating the timely destruction of aberrant proteins, these complementary pathways keep the intracellular environment free of inherently toxic protein aggregates. Chemical interference with the UPS or autophagy has emerged as a viable strategy for therapeutically targeting malignant cells which, owing to their hyperactive state, heavily rely on the sanitizing activity of these proteolytic systems. Here, we report on the discovery of CBK79, a novel compound that impairs both protein degradation by the UPS and autophagy. While CBK79 was identified in a high-content screen for drug-like molecules that inhibit the UPS, subsequent analysis revealed that this compound also compromises autophagic degradation of long-lived proteins. We show that CBK79 induces non-canonical lipidation of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta) that requires ATG16L1 but is independent of the ULK1 (unc-51 like autophagy activating kinase 1) and class III phosphatidylinositol 3-kinase (PtdIns3K) complexes. Thermal preconditioning of cells prevented CBK79-induced UPS impairment but failed to restore autophagy, indicating that activation of stress responses does not allow cells to bypass the inhibitory effect of CBK79 on autophagy. The identification of a small molecule that simultaneously impairs the two main proteolytic systems for protein quality control provides a starting point for the development of a novel class of proteostasis-targeting drugs.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Nyckelord
- Autophagy
- compound screen
- inhibitor
- proteostasis
- stress response
- ubiquitin-proteasome system
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Giovannucci, Tat ...
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Salomons, Floria ...
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Stoy, Henriette
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Herzog, Laura K.
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Xu, Shanshan
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Qian, Weixing
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visa fler...
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Merino, Lara G.
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Gierisch, Maria ...
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Haraldsson, Mart ...
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Lystad, Alf H.
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Uvell, Hanna
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Simonsen, Anne
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Gustavsson, Anna ...
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Vallin, Michaela
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Dantuma, Nico P.
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- Artiklar i publikationen
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Autophagy
- Av lärosätet
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Umeå universitet
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Karolinska Institutet