Limits...
Stat3 controls cell death during mammary gland involution by regulating uptake of milk fat globules and lysosomal membrane permeabilization.

Sargeant TJ, Lloyd-Lewis B, Resemann HK, Ramos-Montoya A, Skepper J, Watson CJ - Nat. Cell Biol. (2014)

Bottom Line: We show here that Stat3 regulates the formation of large lysosomal vacuoles that contain triglyceride.Furthermore, we demonstrate that milk fat globules (MFGs) are toxic to epithelial cells and that, when applied to purified lysosomes, the MFG hydrolysate oleic acid potently induces lysosomal leakiness.Additionally, uptake of secreted MFGs coated in butyrophilin 1A1 is diminished in Stat3-ablated mammary glands and loss of the phagocytosis bridging molecule MFG-E8 results in reduced leakage of cathepsins in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Cambridge, Tennis Court Road Cambridge CB2 1QP, UK.

ABSTRACT
We have previously demonstrated that Stat3 regulates lysosomal-mediated programmed cell death (LM-PCD) during mouse mammary gland involution in vivo. However, the mechanism that controls the release of lysosomal cathepsins to initiate cell death in this context has not been elucidated. We show here that Stat3 regulates the formation of large lysosomal vacuoles that contain triglyceride. Furthermore, we demonstrate that milk fat globules (MFGs) are toxic to epithelial cells and that, when applied to purified lysosomes, the MFG hydrolysate oleic acid potently induces lysosomal leakiness. Additionally, uptake of secreted MFGs coated in butyrophilin 1A1 is diminished in Stat3-ablated mammary glands and loss of the phagocytosis bridging molecule MFG-E8 results in reduced leakage of cathepsins in vivo. We propose that Stat3 regulates LM-PCD in mouse mammary gland by switching cellular function from secretion to uptake of MFGs. Thereafter, perturbation of lysosomal vesicle membranes by high levels of free fatty acids results in controlled leakage of cathepsins culminating in cell death.

Show MeSH

Related in: MedlinePlus

A schematic model illustrating the role of Stat3 in regulating the transition from a secretory to a phagocytic cell phenotype at the onset of involution. Subsequent cell death ensues due to LMP caused by increase in lysosomal size and generation of free fatty acids from hydrolysis of phagocytosed MFGs within lysosomal vacuoles and leakage of cathepsins into a Spi2a cathepsin inhibitor depleted cytosol.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4216597&req=5

Figure 8: A schematic model illustrating the role of Stat3 in regulating the transition from a secretory to a phagocytic cell phenotype at the onset of involution. Subsequent cell death ensues due to LMP caused by increase in lysosomal size and generation of free fatty acids from hydrolysis of phagocytosed MFGs within lysosomal vacuoles and leakage of cathepsins into a Spi2a cathepsin inhibitor depleted cytosol.

Mentions: Thus, we propose a model for Stat3 mediated cell death during involution, which encompasses this switch in mammary epithelial phenotype from a secretory cell to non-professional phagocyte (Fig. 8). To embrace this role, Stat3 powerfully enhances the lysosomal system while at the same time suppressing expression of the protective cytosolic protease inhibitor Spi2a. Uptake of triglyceride and delivery to lysosomes, with subsequent production of fatty acids, results in permeabilisation of large lysosomal vacuoles. The consequent leakage of cathepsin proteases into the cytosol is the final fatal step that causes physiological LM-PCD in the involuting mammary gland (Fig. 8).


Stat3 controls cell death during mammary gland involution by regulating uptake of milk fat globules and lysosomal membrane permeabilization.

Sargeant TJ, Lloyd-Lewis B, Resemann HK, Ramos-Montoya A, Skepper J, Watson CJ - Nat. Cell Biol. (2014)

A schematic model illustrating the role of Stat3 in regulating the transition from a secretory to a phagocytic cell phenotype at the onset of involution. Subsequent cell death ensues due to LMP caused by increase in lysosomal size and generation of free fatty acids from hydrolysis of phagocytosed MFGs within lysosomal vacuoles and leakage of cathepsins into a Spi2a cathepsin inhibitor depleted cytosol.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4216597&req=5

Figure 8: A schematic model illustrating the role of Stat3 in regulating the transition from a secretory to a phagocytic cell phenotype at the onset of involution. Subsequent cell death ensues due to LMP caused by increase in lysosomal size and generation of free fatty acids from hydrolysis of phagocytosed MFGs within lysosomal vacuoles and leakage of cathepsins into a Spi2a cathepsin inhibitor depleted cytosol.
Mentions: Thus, we propose a model for Stat3 mediated cell death during involution, which encompasses this switch in mammary epithelial phenotype from a secretory cell to non-professional phagocyte (Fig. 8). To embrace this role, Stat3 powerfully enhances the lysosomal system while at the same time suppressing expression of the protective cytosolic protease inhibitor Spi2a. Uptake of triglyceride and delivery to lysosomes, with subsequent production of fatty acids, results in permeabilisation of large lysosomal vacuoles. The consequent leakage of cathepsin proteases into the cytosol is the final fatal step that causes physiological LM-PCD in the involuting mammary gland (Fig. 8).

Bottom Line: We show here that Stat3 regulates the formation of large lysosomal vacuoles that contain triglyceride.Furthermore, we demonstrate that milk fat globules (MFGs) are toxic to epithelial cells and that, when applied to purified lysosomes, the MFG hydrolysate oleic acid potently induces lysosomal leakiness.Additionally, uptake of secreted MFGs coated in butyrophilin 1A1 is diminished in Stat3-ablated mammary glands and loss of the phagocytosis bridging molecule MFG-E8 results in reduced leakage of cathepsins in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Cambridge, Tennis Court Road Cambridge CB2 1QP, UK.

ABSTRACT
We have previously demonstrated that Stat3 regulates lysosomal-mediated programmed cell death (LM-PCD) during mouse mammary gland involution in vivo. However, the mechanism that controls the release of lysosomal cathepsins to initiate cell death in this context has not been elucidated. We show here that Stat3 regulates the formation of large lysosomal vacuoles that contain triglyceride. Furthermore, we demonstrate that milk fat globules (MFGs) are toxic to epithelial cells and that, when applied to purified lysosomes, the MFG hydrolysate oleic acid potently induces lysosomal leakiness. Additionally, uptake of secreted MFGs coated in butyrophilin 1A1 is diminished in Stat3-ablated mammary glands and loss of the phagocytosis bridging molecule MFG-E8 results in reduced leakage of cathepsins in vivo. We propose that Stat3 regulates LM-PCD in mouse mammary gland by switching cellular function from secretion to uptake of MFGs. Thereafter, perturbation of lysosomal vesicle membranes by high levels of free fatty acids results in controlled leakage of cathepsins culminating in cell death.

Show MeSH
Related in: MedlinePlus