Format

Send to

Choose Destination
See comment in PubMed Commons below
Nat Chem Biol. 2014 Nov;10(11):969-76. doi: 10.1038/nchembio.1639. Epub 2014 Sep 28.

Unraveling the mechanism of cell death induced by chemical fibrils.

Author information

  • 1Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, California, USA.
  • 21] Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, California, USA. [2] Howard Hughes Medical Institute, University of California-San Francisco, San Francisco, California, USA.
  • 3Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, California, USA.
  • 4Department of Bioengineering and Therapeutic Sciences, University of California-San Francisco, San Francisco, California, USA.
  • 5Department of Biological Sciences, Columbia University, New York, New York, USA.
  • 6Department of Chemistry, University of California-San Diego, San Diego, California, USA.
  • 71] Department of Biological Sciences, Columbia University, New York, New York, USA. [2] Department of Chemistry, Columbia University, New York, New York, USA. [3] Howard Hughes Medical Institute, Columbia University, New York, New York, USA.
  • 81] Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, California, USA. [2] Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, California, USA.

Abstract

We previously discovered a small-molecule inducer of cell death, named 1541, that noncovalently self-assembles into chemical fibrils ('chemi-fibrils') and activates procaspase-3 in vitro. We report here that 1541-induced cell death is caused by the fibrillar rather than the soluble form of the drug. A short hairpin RNA screen reveals that knockdown of genes involved in endocytosis, vesicle trafficking and lysosomal acidification causes partial 1541 resistance. We confirm the role of these pathways using pharmacological inhibitors. Microscopy shows that the fluorescent chemi-fibrils accumulate in punctae inside cells that partially colocalize with lysosomes. Notably, the chemi-fibrils bind and induce liposome leakage in vitro, suggesting they may do the same in cells. The chemi-fibrils induce extensive proteolysis including caspase substrates, yet modulatory profiling reveals that chemi-fibrils form a distinct class from existing inducers of cell death. The chemi-fibrils share similarities with proteinaceous fibrils and may provide insight into their mechanism of cellular toxicity.

PMID:
25262416
PMCID:
PMC4201873
DOI:
10.1038/nchembio.1639
[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Support Center