Yu Tae-Geun, Cha Jeong Seok, Kim Gijeong, Sohn Yoo-Kyoung, Yoo Youngki, Kim Uijin, Song Ji-Joon, Cho Hyun-Soo, Kim Hak-Sung
Departement of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea.
Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Korea.
Cell Death Discov. 2023 Apr 29;9(1):142. doi: 10.1038/s41420-023-01438-6.
Inflammasomes are multi-protein complexes and play a crucial role in host defense against pathogens. Downstream inflammatory responses through inflammasomes are known to be related to the oligomerization degree of ASC specks, but the detailed mechanism still remains unexplored. Here, we demonstrate that oligomerization degrees of ASC specks regulate the caspase-1 activation in the extracellular space. A protein binder specific for a pyrin domain (PYD) of ASC (ASC) was developed, and structural analysis revealed that the protein binder effectively inhibits the interaction between PYDs, disassembling ASC specks into low oligomeric states. ASC specks with a low oligomerization degree were shown to enhance the activation of caspase-1 by recruiting and processing more premature caspase-1 through interactions between CARD of caspase-1 (caspase-1) and CARD of ASC (ASC). These findings can provide insight into controlling the inflammasome-mediated inflammatory process as well as the development of inflammasome-targeting drugs.
炎症小体是多蛋白复合物，在宿主抵御病原体的过程中发挥关键作用。已知通过炎症小体的下游炎症反应与ASC斑点的寡聚化程度有关，但详细机制仍未得到探索。在此，我们证明ASC斑点的寡聚化程度调节细胞外空间中的半胱天冬酶-1激活。开发了一种对ASC的吡喃结构域（PYD）具有特异性的蛋白结合剂，结构分析表明该蛋白结合剂有效抑制PYD之间的相互作用，将ASC斑点分解为低寡聚状态。低寡聚化程度的ASC斑点通过半胱天冬酶-1（caspase-1）的CARD与ASC（ASC）的CARD之间的相互作用招募和加工更多的前体半胱天冬酶-1，从而增强半胱天冬酶-1的激活。这些发现可为控制炎症小体介导的炎症过程以及开发靶向炎症小体的药物提供见解。
