Editors' ChoiceTissue Reorganization

Switching from Secretory to Phagocytic

Science Signaling  25 Nov 2014:
Vol. 7, Issue 353, pp. ec326
DOI: 10.1126/scisignal.aaa3287

Within the acidic environment of lysosomes, cellular constituents are degraded by proteases, such as cathepsin. Permeabilization of lysosomal membranes can trigger cell death, such as occurs during the shrinking of milk-producing mammary epithelial cells when lactation ends, a process called involution. Involution of mammary tissues requires signaling through the transcription factor Stat3 to stimulate the expression of genes encoding cathepsin isoforms and repress the expression of a gene encoding a cathepsin inhibitor. Sargeant et al. (see also Krishna and Overholtzer) investigated how Stat3 triggers lysosomal membrane permeabilization. Large lysosomal vacuoles were more numerous in epithelial cells in involuting mammary glands of control mice compared to those of mice with a luminal epithelial-specific knockout of Stat3 (Stat3 KO mice). These vacuoles stained for cathepsin D and contained autophagic vesicles, milk proteins, and triglycerides. Oncostatin M, a cytokine that activates Stat3 during involution, triggered vacuole formation when applied to EpH4 cells, a mammary epithelial cell line. When mouse milk was added to the culture medium, vacuoles in EpH4 cells accumulated lipids and the cells died. The addition of bafilomycin A1, which prevents lysosomal acidification, prevented cell death in response to milk. Testing of various constituents in milk revealed that EphH4 cells died when exposed to oleic or palmitic acid. Incubation of cytosolic fractions with oleic acid triggered the release of cathepsins from lysosomes; the extent of cathepsin release was less with palmitic acid incubation. Application of oleic acid to purified lysosomes induced lysosomal permeabilization. Secreted milk fat globules are coated with butyrophilin 1A1 (BTN), and the involuting mammary glands of Stat3 KO mice took up fewer BTN-coated milk fat globules than those of control mice. BTN-coated milk fat globules were taken up by macropinocytosis and phagocytosis. However, mice lacking a protein required for phagocytosis showed decreased release of cathepsins during involution. These results suggest that Stat3 switches mammary epithelial cells from secretory cells to phagocytic cells during involution. Furthermore, the cellular uptake of milk fat globules, in particular oleic acid, triggers lysosomal permeabilization, leading to cathepsin release and cell death.

T. J. Sargeant, B. Lloyd-Lewis, H. K. Resemann, A. Ramos-Montoya, J. Skepper, C. J. Watson, Stat3 controls cell death during mammary gland involution by regulating uptake of milk fat globules and lysosomal membrane permeabilization. Nat. Cell Biol. 16, 1057–1068 (2014). [PubMed]

S. Krishna, M. Overholtzer, Milk makes lysosomes lethal. Nat. Cell Biol. 16, 1029–1031 (2014). [PubMed]

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