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

Author:

Yokoyama, Shigetoshi [ORCID]

Cai, Yan

Murata, Miyuki

Tomita, Takeshi

Yoneda, Mitsuhiro

Xu, Lei

Pilon, Aprile L

Cachau, Raul

Kimura, Shioko [ORCID]
Author Address

Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, United States., APCBIo Innovations Inc., Rockville, United States., Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Leidos Biomedical Inc., Frederick, United States.,

Abstract:

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.

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