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Beta-sheet-specific interactions with heat shock proteins define a mechanism of delayed tumor cell death in response to HAMLET

Nadeem, Aftab LU ; Ho, James C.S. ; Tran, Tuan Hiep ; Paul, Sanchari LU ; Granqvist, Victoria LU ; Despretz, Nadege and Svanborg, Catharina LU (2019) In Journal of Molecular Biology 431(14). p.2612-2627
Abstract

As chaperones, heat shock proteins (HSPs)protect host cells against misfolded proteins that constitute a by-product of protein synthesis. Certain HSPs are also expressed on the surface of tumor cells, possibly to scavenge extracellular unfolded protein ligands and prevent them from becoming cytotoxic. HAMLET—a complex of partially unfolded alpha-lactalbumin and oleic acid—is relying on its N-terminal alpha-helical domain to perturb tumor cell membranes, and the cells die as a consequence of this interaction. Here we show that in parallel, cell surface HSPs bind the beta-sheet domain of alpha-lactalbumin and activate a temporarily protective loop, involving vesicular uptake and lysosomal accumulation. Later, HAMLET destroys lysosomal... (More)

As chaperones, heat shock proteins (HSPs)protect host cells against misfolded proteins that constitute a by-product of protein synthesis. Certain HSPs are also expressed on the surface of tumor cells, possibly to scavenge extracellular unfolded protein ligands and prevent them from becoming cytotoxic. HAMLET—a complex of partially unfolded alpha-lactalbumin and oleic acid—is relying on its N-terminal alpha-helical domain to perturb tumor cell membranes, and the cells die as a consequence of this interaction. Here we show that in parallel, cell surface HSPs bind the beta-sheet domain of alpha-lactalbumin and activate a temporarily protective loop, involving vesicular uptake and lysosomal accumulation. Later, HAMLET destroys lysosomal membrane integrity, and HAMLET release kills the remaining tumor cells. HSPs were identified as HAMLET targets in a proteomic screen and Hsp70-specific antibodies or shRNAs inhibited HAMLET uptake by tumor cells, which showed increased Hsp70 surface expression compared to differentiated cells. The results suggest that HAMLET engages tumor cells by two parallel recognition mechanisms, defined by alpha-helical- or beta-sheet domains of alpha-lactalbumin and resulting in an immediate death response, or a delay due to transient accumulation of the complex in the lysosomes. This dual response pattern was conserved among tumor cells but not seen in normal, differentiated cells. By two different mechanisms, HAMLET thus achieves a remarkably efficient elimination of tumor cells.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
beta peptide, lysosome, scavenger, tumoricidal activity, unfolded protein
in
Journal of Molecular Biology
volume
431
issue
14
pages
2612 - 2627
publisher
Elsevier
external identifiers
  • pmid:31082436
  • scopus:85066256510
ISSN
0022-2836
DOI
10.1016/j.jmb.2019.05.007
language
English
LU publication?
yes
id
87676f18-0308-4bdf-b3f4-226eaac5960f
date added to LUP
2019-06-14 13:56:49
date last changed
2024-04-30 12:44:27
@article{87676f18-0308-4bdf-b3f4-226eaac5960f,
  abstract     = {{<p>As chaperones, heat shock proteins (HSPs)protect host cells against misfolded proteins that constitute a by-product of protein synthesis. Certain HSPs are also expressed on the surface of tumor cells, possibly to scavenge extracellular unfolded protein ligands and prevent them from becoming cytotoxic. HAMLET—a complex of partially unfolded alpha-lactalbumin and oleic acid—is relying on its N-terminal alpha-helical domain to perturb tumor cell membranes, and the cells die as a consequence of this interaction. Here we show that in parallel, cell surface HSPs bind the beta-sheet domain of alpha-lactalbumin and activate a temporarily protective loop, involving vesicular uptake and lysosomal accumulation. Later, HAMLET destroys lysosomal membrane integrity, and HAMLET release kills the remaining tumor cells. HSPs were identified as HAMLET targets in a proteomic screen and Hsp70-specific antibodies or shRNAs inhibited HAMLET uptake by tumor cells, which showed increased Hsp70 surface expression compared to differentiated cells. The results suggest that HAMLET engages tumor cells by two parallel recognition mechanisms, defined by alpha-helical- or beta-sheet domains of alpha-lactalbumin and resulting in an immediate death response, or a delay due to transient accumulation of the complex in the lysosomes. This dual response pattern was conserved among tumor cells but not seen in normal, differentiated cells. By two different mechanisms, HAMLET thus achieves a remarkably efficient elimination of tumor cells.</p>}},
  author       = {{Nadeem, Aftab and Ho, James C.S. and Tran, Tuan Hiep and Paul, Sanchari and Granqvist, Victoria and Despretz, Nadege and Svanborg, Catharina}},
  issn         = {{0022-2836}},
  keywords     = {{beta peptide; lysosome; scavenger; tumoricidal activity; unfolded protein}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{14}},
  pages        = {{2612--2627}},
  publisher    = {{Elsevier}},
  series       = {{Journal of Molecular Biology}},
  title        = {{Beta-sheet-specific interactions with heat shock proteins define a mechanism of delayed tumor cell death in response to HAMLET}},
  url          = {{http://dx.doi.org/10.1016/j.jmb.2019.05.007}},
  doi          = {{10.1016/j.jmb.2019.05.007}},
  volume       = {{431}},
  year         = {{2019}},
}