期刊
NATURE CHEMICAL BIOLOGY
卷 10, 期 11, 页码 969-976出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1639
关键词
-
资金
- US National Institutes of Health [R01 CA136779, R01 CA097061, F32AI095062]
- Howard Hughes Medical Institute
- Achievement Rewards for College Scientists Foundation Award
- Schleroderma Research Foundation Evnin-Wright Fellowship
- Jane Coffin Childs Memorial Fund
- Canadian Institutes of Health Research
- Government of Canada
- University of California-San Francisco Program for Breakthrough Biomedical Research
- Sandler Foundation
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据