免疫システムの中心成分の構造が明らかに(Structure of a central component of the human immune system revealed)

2023-12-08

2023-12-07 ミュンヘン大学(LMU)

◆NLRP3インフラマソームは感染と戦う免疫系の一環であり、慢性的な活性化がアルツハイマーやパーキンソン病、多発性硬化症などに関連しています。ASCタンパク質はこの複合体の中心的な要素で、新たな研究ではこれの3D構造が光学顕微鏡を用いて初めて視覚化されました。
◆ASCスペックは非定型で、密な中心から周辺にフィラメントが伸びています。異なるラベリング手法を組み合わせてこれを実現し、高分解能蛍光顕微鏡を用いて密な構造をイメージングする重要な洞察が得られました。

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内因性ASC斑点のナノスケール組織化 Nanoscale organization of the endogenous ASC speck

Ivo M. Glück,Grusha Primal Mathias,Sebastian Strauss,Virgile Rat,Irene Gialdini,Thomas Sebastian Ebert,Che Stafford,Ganesh Agam,Suliana Manley,Veit Hornung,Ralf Jungmann,Christian Sieben,Don C. Lamb
iScience Published:November 03, 2023
DOI:https://doi.org/10.1016/j.isci.2023.108382

Highlights

•Structure of ASC speck investigated under conditions of endogenous ASC expression
•Combined antibody and nanobody labeling required to obtain complete ASC structure
•The ASC speck is roughly spherical with dense core and emerging filaments
•The ASC speck becomes denser but not larger during its formation

Summary

The NLRP3 inflammasome is a central component of the innate immune system. Its activation leads to formation of the ASC speck, a supramolecular assembly of the inflammasome adaptor protein ASC. Different models, based on ASC overexpression, have been proposed for the structure of the ASC speck. Using dual-color 3D super-resolution imaging (dSTORM and DNA-PAINT), we visualized the ASC speck structure following NLRP3 inflammasome activation using endogenous ASC expression. A complete structure was only obtainable by labeling with both anti-ASC antibodies and nanobodies. The complex varies in diameter between ∼800 and 1000 nm, and is composed of a dense core with emerging filaments. Dual-color confocal fluorescence microscopy indicated that the ASC speck does not colocalize with the microtubule-organizing center at late time points after Nigericin stimulation. From super-resolution images of whole cells, the ASC specks were sorted into a pseudo-time sequence indicating that they become denser but not larger during formation.