Changes in proteasome structure and function caused by HAMLET in tumor cells.

Research output: Contribution to journalArticle


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 alpha-lactalbumin. After a brief activation, HAMLET inhibited proteasome activity in vitro and in parallel a change in proteasome structure occurred, with modifications of catalytic (beta1 and beta5) and structural subunits (alpha2, alpha3, alpha6 and beta3). 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.


Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Microbiology in the medical area
  • Immunology in the medical area
  • Rheumatology and Autoimmunity
Original languageEnglish
Article numbere5229
JournalPLoS ONE
Issue number4
Publication statusPublished - 2009
Publication categoryResearch

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Division of Microbiology, Immunology and Glycobiology - MIG (013025200), Connective Tissue Biology (013230151)

Total downloads

No data available

Related research output

Lotta Gustafsson, Oskar Hallgren, Barbara Spolaore, Carol Robinsson & Catharina Svanborg, 2006, In : IDrugs. 9, 3, p. B29

Research output: Contribution to journalPublished meeting abstract

Lotta Gustafsson, 2002 Oct 6.

Research output: Contribution to conferenceAbstract

View all (2)

Related projects

Lotta Gustafsson


Project: ResearchInternational collaboration

Lotta Gustafsson


Project: DissertationInternational collaboration, National collaboration, Teaching, Collaboration with industry

View all (2)

Related activities

Gustafsson, L. (Visiting researcher)
2007 Sep 12007 Dec 31

Activity: Visiting an external institutionResearch or teaching at external organisation

Gustafsson, L. (Joint first/primary/lead supervisor)
2006 Jun2007 Dec

Activity: Examination and supervisionSupervision of PhD students

Gustafsson, L. (Invited speaker)
2006 Jan 182006 Jan 22

Activity: Talk or presentationPresentation

View all (6)

Related prizes

Lotta Gustafsson (Recipient), 2008 Feb 13

Prizes and Distinctions: Prize (including medals and awards)

View all (1)