Stat3 controls lysosomal-mediated cell death in vivo

Kreuzaler, Peter A., Staniszewska, Anna D., Li, Wenjing, Omidvar, Nader, Kedjouar, Blandine, Turkson, James, Poli, Valeria, Flavell, Richard A., Clarkson, Richard W. E. ORCID: https://orcid.org/0000-0001-7389-8673 and Watson, Christine J. 2011. Stat3 controls lysosomal-mediated cell death in vivo. Nature Cell Biology 13 (3) , pp. 303-309. 10.1038/ncb2171

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Abstract

It is well established that lysosomes play an active role during the execution of cell death1. A range of stimuli can lead to lysosomal membrane permeabilization (LMP), thus inducing programmed cell death without involvement of the classical apoptotic programme2, 3. However, these lysosomal pathways of cell death have mostly been described in vitro or under pathological conditions4, 5, 6, 7. Here we show that the physiological process of post-lactational regression of the mammary gland is accomplished through a non-classical, lysosomal-mediated pathway of cell death. We found that, during involution, lysosomes in the mammary epithelium undergo widespread LMP. Furthermore, although cell death through LMP is independent of executioner caspases 3, 6 and 7, it requires Stat3, which upregulates the expression of lysosomal proteases cathepsin B and L, while downregulating their endogenous inhibitor Spi2A (ref. 8). Our findings report a previously unknown, Stat3-regulated lysosomal-mediated pathway of cell death under physiological circumstances. We anticipate that these findings will be of major importance in the design of treatments for cancers such as breast, colon and liver, where cathepsins and Stat3 are commonly overexpressed and/or hyperactivated respectively1, 9, 10.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Medicine European Cancer Stem Cell Research Institute (ECSCRI)
Subjects:	Q Science > QH Natural history > QH301 Biology R Medicine > R Medicine (General)
Publisher:	NPG
ISSN:	1465-7392
Last Modified:	22 Jun 2023 10:01
URI:	https://orca.cardiff.ac.uk/id/eprint/9874

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