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Multiple excitable signaling dynamics regulate pseudopod formation in eukaryotic chemotaxis

田鍋, 友紀 大阪大学 DOI:10.18910/77465

2020.06.19

概要

細胞は外部環境にある化学物質の濃度勾配を感知し、仮足を形成して進む性質を有している。走化性と呼ばれるこの性質は発生や免疫応答、がん細胞の浸潤など様々な生命現象で機能しており、生物によって必須な能力である。真核生物の細胞性粘菌を用いた走化性研究から、細胞の仮足形成はsGC(グアニル酸シクラーゼ)経路やPIP3経路、そしてTorC経路といった複数のシグナル伝達経路によって時空間的に制御されていることが分かっている。各経路のシグナル分子が仮足となる部分に局在し、細胞骨格の構造変化を引き起こすことで仮足が形成されるが、近年シグナル分子の1つであるPIP3局在が興奮系様の応答を示すことが明らかとなった。更に、その性質は進化的に保存されており、仮足形成における興奮性の役割が注目されている。PIP3経路については詳細な解析が進んでいるものの、他の経路の応答性との比較や、複数のシグナル伝達経路が細胞の仮足形成をどのように調節しているのかは調べられてこなかった。

本研究では、生細胞の蛍光イメージングによりsGC局在応答の定量解析を行った。その結果、 sGC局在が興奮系の特徴である0/1応答や不応期を示し、PIP3だけでなくsGC局在もまた興奮性のシグナル伝達経路であることを明らかとした。特に、sGC局在の方がPIP3局在より短い不応期を有しており、より速く外部環境への変動に応答可能であることが分かった。また、sGCの酵素活性により合成された細胞内cGMP及びcGMPに結合するタンパク質GbpCが、sGC局在やActin重合を抑制していることを見出した。このネガティブフィードバック制御がsGC局在の不応期を決定づけてお り、細胞の仮足形成を制御していることを示した。これらの結果を踏まえ、sGCとPIP3の同時イメージングを行うことで、細胞の仮足伸長が異なる不応期をもつ興奮性シグナル経路によって加算的に調節されていることを明らかとした。今後の課題は、sGC局在が有する興奮性の数理的解析と、複数の興奮性シグナル経路の走化性への寄与を明らかにすることである。

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