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Changes in Proteasome Structure and Function Caused by HAMLET in Tumor Cells
BACKGROUND: Proteasomes control the level of endogenous unfolded proteins by degrading them in the proteolytic core. Insufficient degradation due to altered protein structure or proteasome inhibition may trigger cell death. This study examined the proteasome response to HAMLET, a partially unfolded...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664966/ https://www.ncbi.nlm.nih.gov/pubmed/19365565 http://dx.doi.org/10.1371/journal.pone.0005229 |
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author | Gustafsson, Lotta Aits, Sonja Önnerfjord, Patrik Trulsson, Maria Storm, Petter Svanborg, Catharina |
author_facet | Gustafsson, Lotta Aits, Sonja Önnerfjord, Patrik Trulsson, Maria Storm, Petter Svanborg, Catharina |
author_sort | Gustafsson, Lotta |
collection | PubMed |
description | BACKGROUND: Proteasomes control the level of endogenous unfolded proteins by degrading them in the proteolytic core. Insufficient degradation due to altered protein structure or proteasome inhibition may trigger cell death. This study examined the proteasome response to HAMLET, a partially unfolded protein-lipid complex, which is internalized by tumor cells and triggers cell death. METHODOLOGY/PRINCIPAL FINDINGS: HAMLET bound directly to isolated 20S proteasomes in vitro and in tumor cells significant co-localization of HAMLET and 20S proteasomes was detected by confocal microscopy. This interaction was confirmed by co-immunoprecipitation from extracts of HAMLET-treated tumor cells. HAMLET resisted in vitro degradation by proteasomal enzymes and degradation by intact 20S proteasomes was slow compared to fatty acid-free, partially unfolded α-lactalbumin. After a brief activation, HAMLET inhibited proteasome activity in vitro and in parallel a change in proteasome structure occurred, with modifications of catalytic (β1 and β5) and structural subunits (α2, α3, α6 and β3). Proteasome inhibition was confirmed in extracts from HAMLET-treated cells and there were indications of proteasome fragmentation in HAMLET-treated cells. CONCLUSIONS/SIGNIFICANCE: The results suggest that internalized HAMLET is targeted to 20S proteasomes, that the complex resists degradation, inhibits proteasome activity and perturbs proteasome structure. We speculate that perturbations of proteasome structure might contribute to the cytotoxic effects of unfolded protein complexes that invade host cells. |
format | Text |
id | pubmed-2664966 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-26649662009-04-14 Changes in Proteasome Structure and Function Caused by HAMLET in Tumor Cells Gustafsson, Lotta Aits, Sonja Önnerfjord, Patrik Trulsson, Maria Storm, Petter Svanborg, Catharina PLoS One Research Article BACKGROUND: Proteasomes control the level of endogenous unfolded proteins by degrading them in the proteolytic core. Insufficient degradation due to altered protein structure or proteasome inhibition may trigger cell death. This study examined the proteasome response to HAMLET, a partially unfolded protein-lipid complex, which is internalized by tumor cells and triggers cell death. METHODOLOGY/PRINCIPAL FINDINGS: HAMLET bound directly to isolated 20S proteasomes in vitro and in tumor cells significant co-localization of HAMLET and 20S proteasomes was detected by confocal microscopy. This interaction was confirmed by co-immunoprecipitation from extracts of HAMLET-treated tumor cells. HAMLET resisted in vitro degradation by proteasomal enzymes and degradation by intact 20S proteasomes was slow compared to fatty acid-free, partially unfolded α-lactalbumin. After a brief activation, HAMLET inhibited proteasome activity in vitro and in parallel a change in proteasome structure occurred, with modifications of catalytic (β1 and β5) and structural subunits (α2, α3, α6 and β3). Proteasome inhibition was confirmed in extracts from HAMLET-treated cells and there were indications of proteasome fragmentation in HAMLET-treated cells. CONCLUSIONS/SIGNIFICANCE: The results suggest that internalized HAMLET is targeted to 20S proteasomes, that the complex resists degradation, inhibits proteasome activity and perturbs proteasome structure. We speculate that perturbations of proteasome structure might contribute to the cytotoxic effects of unfolded protein complexes that invade host cells. Public Library of Science 2009-04-14 /pmc/articles/PMC2664966/ /pubmed/19365565 http://dx.doi.org/10.1371/journal.pone.0005229 Text en Gustafsson et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Gustafsson, Lotta Aits, Sonja Önnerfjord, Patrik Trulsson, Maria Storm, Petter Svanborg, Catharina Changes in Proteasome Structure and Function Caused by HAMLET in Tumor Cells |
title | Changes in Proteasome Structure and Function Caused by HAMLET in Tumor Cells |
title_full | Changes in Proteasome Structure and Function Caused by HAMLET in Tumor Cells |
title_fullStr | Changes in Proteasome Structure and Function Caused by HAMLET in Tumor Cells |
title_full_unstemmed | Changes in Proteasome Structure and Function Caused by HAMLET in Tumor Cells |
title_short | Changes in Proteasome Structure and Function Caused by HAMLET in Tumor Cells |
title_sort | changes in proteasome structure and function caused by hamlet in tumor cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664966/ https://www.ncbi.nlm.nih.gov/pubmed/19365565 http://dx.doi.org/10.1371/journal.pone.0005229 |
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