Cell death

Death by Lysosome

Science Signaling  08 Mar 2011:
Vol. 4, Issue 163, pp. ec65
DOI: 10.1126/scisignal.4163ec65

Involution of the mammary gland after weaning is a major cell death phenomenon in adult animals. Kreuzaler et al. performed temporal analysis of mouse mammary gland involution and found two distinct phases: An early reversible phase did not appear to involve apoptosis (no TUNEL-positive cells, no active caspase-7, and no morphological characteristics of apoptosis), and a later irreversible phase exhibited hallmarks of classical apoptosis (TUNEL-positive cells and caspase-7 activity). Mice in which caspases 3 and 6 were knocked out or mice expressing an inhibitor of caspases (p35) in the mammary gland showed normal involution. The abundance of the lysosomal membrane protein LAMP2 was decreased during lactation and until the second day of involution. The abundance and activity of cathepsins B and L were increased at the onset of involution, and the colocalization of cathepsin B with LAMP2 was decreased at the onset of involution, suggesting that increased lysosomal membrane permeability may contribute to cell death associated with involution. Subcellular fractionation experiments confirmed that cathepsin B and L activity was increased in the cytosol, and in vitro experiments with isolated lysosomes showed that the lysosomes from glands undergoing involution had increased permeability compared with lysosomes from glands of lactating mice. The transcription factor Stat3 had been previously implicated in mammary gland involution. The authors found that Stat3 mammary gland conditional knockout mice had markedly reduced transcript and protein abundance and lower cytosolic activity of cathepsin B and L during involution, despite increased lysosomal leakiness. Stat3-knockout mice also showed increased transcription of the gene encoding Spi2A, a serpin that inhibits cathepsin activity. Treatment of mice with a cathepsin inhibitor delayed involution. The Stat3-mediated lysosomal cell death pathway was recapitulated in cultured mammary epithelial cells by treating the cells with the cytokine OSM to activate Stat3 and was inhibited with a small-molecule inhibitor of Stat3. Thus, mammary gland involution relies on a controlled necrotic death pathway (see Luke and Silverman for commentary).

P. A. Kreuzaler, A. D. Staniszewska, W. Li, N. Omidvar, B. Kedjouar, J. Turkson, V. Poli, R. A. Flavell, R. W. E. Clarkson, C. J. Watson, Stat3 controls lysosomal-mediated cell death in vivo. Nat. Cell Biol. 13, 303–309 (2011). [PubMed]

C. J. Luke, G. A. Silverman, Necrotic cell death: Harnessing the Dark side of the Force in mammary gland involution. Nat. Cell Biol. 13, 197–199 (2011). [PubMed]