A novel pathway of LPS uptake through syndecan-1 leading to pyroptotic cell death.

Autor:	Yokoyama S; Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, United States., Cai Y; Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, United States., Murata M; Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, United States., Tomita T; Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, United States., Yoneda M; Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, United States., Xu L; Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, United States., Pilon AL; APCBIo Innovations Inc., Rockville, United States., Cachau RE; Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Leidos Biomedical Inc., Frederick, United States., Kimura S; Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2018 Dec 07; Vol. 7. Date of Electronic Publication: 2018 Dec 07.
DOI:	10.7554/eLife.37854
Abstrakt:	Intracellular lipopolysaccharide (LPS) triggers the non-canonical inflammasome pathway, resulting in pyroptosis of innate immune cells. In addition to its well-known proinflammatory role, LPS can directly cause regression of some tumors, although the underlying mechanism has remained unknown. Here we show that secretoglobin(SCGB)3A2, a small protein predominantly secreted in airways, chaperones LPS to the cytosol through the cell surface receptor syndecan-1; this leads to pyroptotic cell death driven by caspase-11. SCGB3A2 and LPS co-treatment significantly induced pyroptosis of macrophage RAW264.7 cells and decreased cancer cell proliferation in vitro, while SCGB3A2 treatment resulted in reduced progression of xenograft tumors in mice. These data suggest a conserved function for SCGB3A2 in the innate immune system and cancer cells. These findings demonstrate a critical role for SCGB3A2 as an LPS delivery vehicle; they reveal one mechanism whereby LPS enters innate immune cells leading to pyroptosis, and they clarify the direct effect of LPS on cancer cells. Competing Interests: SY, YC, MM, TT, MY, LX, RC, SK No competing interests declared, AP ALP is an employee of APCBio Innovations and has a 51% ownership interest in APCBio Innovations, which has an interest in commercializing the rhSCGB3A2. US Patent Application (No. 62/619,511) was filed for the work described in this manuscript.
Databáze:	MEDLINE
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