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Stat3 controls lysosomal-mediated cell death in vivo.
Nat Cell Biol. 2011 Mar; 13(3):303-9
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10 Mar 2011
DOI: 10.3410/f.8946956.9504054
This is an interesting study indicating that leaky lysosomes can cause programmed cell death (PCD) under physiological conditions in vivo. The study examined regression of the mouse mammary gland up to 15 days after weaning, a process thought to involve the classical apoptotic form of PCD. However, epithelial...Continue reading
This is an interesting study indicating that leaky lysosomes can cause programmed cell death (PCD) under physiological conditions in vivo. The study examined regression of the mouse mammary gland up to 15 days after weaning, a process thought to involve the classical apoptotic form of PCD. However, epithelial cell death in the first 0-2 days appeared to occur via a lysosome-dependent pathway.
Several changes in the lysosome system were observed in this first, reversible, phase of involution. Production of the cysteine cathepsins B and L (but not the aspartate cathepsin D) was increased, largely due to signal transducer and activator of transcription 3 (Stat3). There was leakage of cathepsins B and L into the cytosol, possibly related to marked downregulation of the structural lysosomal membrane protein LAMP2. Once in the cytosol, cathepsin B and L activity may also be enhanced by the ability of Stat3 to downregulate the serpin Spi2A that specifically inhibits cysteine cathepsins.
The role for cathepsin B in this PCD was also supported by delayed regression of the mammary gland following injection with the cathepsin B inhibitor CA-074Me. In addition, a cathepsin B inhibitor, but not a caspase inhibitor, could block apoptosis of cultured mammary epithelial cells induced by the Stat3 activator, oncostatin M.
It will be important to further delineate each step in this lysosome-dependent pathway of cell death, including whether mitochondrial permeabilization is involved.
Several changes in the lysosome system were observed in this first, reversible, phase of involution. Production of the cysteine cathepsins B and L (but not the aspartate cathepsin D) was increased, largely due to signal transducer and activator of transcription 3 (Stat3). There was leakage of cathepsins B and L into the cytosol, possibly related to marked downregulation of the structural lysosomal membrane protein LAMP2. Once in the cytosol, cathepsin B and L activity may also be enhanced by the ability of Stat3 to downregulate the serpin Spi2A that specifically inhibits cysteine cathepsins.
The role for cathepsin B in this PCD was also supported by delayed regression of the mammary gland following injection with the cathepsin B inhibitor CA-074Me. In addition, a cathepsin B inhibitor, but not a caspase inhibitor, could block apoptosis of cultured mammary epithelial cells induced by the Stat3 activator, oncostatin M.
It will be important to further delineate each step in this lysosome-dependent pathway of cell death, including whether mitochondrial permeabilization is involved.
Disclosures
None declared
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Kluck R and Dewson G: F1000Prime Recommendation of [Kreuzaler PA et al., Nat Cell Biol 2011, 13(3):303-9]. In F1000Prime, 10 Mar 2011; DOI: 10.3410/f.8946956.9504054. F1000Prime.com/8946956#eval9504054
11 Jul 2012
New Finding
DOI: 10.3410/f.8946956.793302840
This paper shows that the lysosomal cell death pathway is essential for the proper regression of the mammary gland after involution in mice. It provides the very first demonstration of lysosomal cell death in normal mammalian physiology.
The role of lysosomes and lysosomal hydrolases in cell death...Continue reading
The role of lysosomes and lysosomal hydrolases in cell death...Continue reading
This paper shows that the lysosomal cell death pathway is essential for the proper regression of the mammary gland after involution in mice. It provides the very first demonstration of lysosomal cell death in normal mammalian physiology.
The role of lysosomes and lysosomal hydrolases in cell death was introduced almost 60 years ago by a Belgian scientist Christian de Duve who was awarded the Nobel Prize for his discovery and characterization of lysosomes. Owing to the potent hydrolytic capacity of lysosomal hydrolases, de Duve defined lysosomes as 'suicide bags' that can cause cell death and tissue damage upon rupture and subsequent release of lysosomal hydrolyses into the cytosol and the extracellular space. Notably, he also suggested that this death pathway would play an important role in developmental and physiological cell death, including mammary gland involution. These suggestions triggered an intensive search for pharmaceutical agents that either stabilized or destabilized lysosomal membranes for the treatment of degenerative disorders and cancer, respectively. Interest in lysosomal cell death pathways waned, however, rapidly. de Duve speculated that this was largely due to the lack of proper assay systems that could differentiate lysosomal rupture, which causes cell death from postmortal alterations in autolytic cells. Unfortunately, over 50 years had to pass before novel more sensitive assays to study lysosomal membrane permeabilization were developed to initiate a new wave of interest in lysosomal cell death pathways and to allow this important discovery.
It will now be important to take advantage of the new technology available to define whether the lysosomal cell death pathway plays a role also in other physiological cell death processes.
The role of lysosomes and lysosomal hydrolases in cell death was introduced almost 60 years ago by a Belgian scientist Christian de Duve who was awarded the Nobel Prize for his discovery and characterization of lysosomes. Owing to the potent hydrolytic capacity of lysosomal hydrolases, de Duve defined lysosomes as 'suicide bags' that can cause cell death and tissue damage upon rupture and subsequent release of lysosomal hydrolyses into the cytosol and the extracellular space. Notably, he also suggested that this death pathway would play an important role in developmental and physiological cell death, including mammary gland involution. These suggestions triggered an intensive search for pharmaceutical agents that either stabilized or destabilized lysosomal membranes for the treatment of degenerative disorders and cancer, respectively. Interest in lysosomal cell death pathways waned, however, rapidly. de Duve speculated that this was largely due to the lack of proper assay systems that could differentiate lysosomal rupture, which causes cell death from postmortal alterations in autolytic cells. Unfortunately, over 50 years had to pass before novel more sensitive assays to study lysosomal membrane permeabilization were developed to initiate a new wave of interest in lysosomal cell death pathways and to allow this important discovery.
It will now be important to take advantage of the new technology available to define whether the lysosomal cell death pathway plays a role also in other physiological cell death processes.
Disclosures
None declared
Jaattela M: F1000Prime Recommendation of [Kreuzaler PA et al., Nat Cell Biol 2011, 13(3):303-9]. In F1000Prime, 11 Jul 2012; DOI: 10.3410/f.8946956.793302840. F1000Prime.com/8946956#eval793302840
F1000Prime Recommendations, Dissents and Comments for [Kreuzaler PA et al., Nat Cell Biol 2011, 13(3):303-9]. In F1000Prime, 20 May 2013; F1000Prime.com/8946956
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It is well established that lysosomes play an active role during the execution of cell death. A range of stimuli can lead to lysosomal membrane permeabilization (LMP), thus inducing programmed cell death without involvement of the classical apoptotic programme. However, these lysosomal pathways of cell death have mostly been described in vitro or under pathological conditions. 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 respectively.
DOI: 10.1038/ncb2171
PMID: 21336304
