H. pyloriのがん蛋白質CagA分解を司るautophagyの宿主細胞シグナルは, VacA受容体であるLRP1が, リソソーム産生亢進を仲介することで, autophagosomeとautolysosomeの融合起点において重要な役割を担うことを明らかとした。さらにLRP1への結合を介して, LRP1によるautophagy発現シグナルを不に制御する分子を見出し, この分子の過剰発現細胞はCagAを特異的に蓄積させるのみならず, CD44v9発現を惹起させることを明らかとした。本研究成果により, CagA蓄積とCD44v9発現亢進に繋がる極めて重要な宿主細胞キャラクターが同定された。
Intracellular CagA is degraded by autophagy. CagA-degradin autophagy was suppressed in CD44v9-expressing host cells, resulting in the specific accumulation of CagA in these cells. This autophagic pathway was activated by VacA via binding to LRP1. During autophagy, LRP1 was translocated to the nuclei, and increased the LAMP1 expression via binding to the lamp1 promoter. Specific knockdown of lamp1 decreased the formation of autophagolysosome, leading to the intracellular accumulation of CagA. Additionally, we identified a LRP1-binding protein which binds to LRP1 in the nuclei and suppresses transcription of LAMP1. In cells overexpressing the LRP1-binding protein, autophagy was suppressed and then CagA accumulated. The accumulation of CagA in LRP1-binding protein overexpressing cells caused increased CD44v9 expressions. The expression levels of the LRP1-binding protein determine the intracellular CagA stability associated with the induction of CD44v9 expression.
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