Institute for Biophysical Chemistry, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
Int J Mol Sci. 2022 Sep 7;23(18):10269. doi: 10.3390/ijms231810269.
The cytosolic immune receptor NLRP3 (nucleotide-binding domain, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3) oligomerizes into the core of a supramolecular complex termed inflammasome in response to microbes and danger signals. It is thought that NLRP3 has to bind NEK7 (NIMA (never in mitosis gene a)-related kinase 7) to form a functional inflammasome core that induces the polymerization of the adaptor protein ASC (Apoptosis-associated speck-like protein containing a CARD (caspase recruitment domain)), which is a hallmark for NLRP3 activity. We reconstituted the NLRP3 inflammasome activity in modified HEK293 (human embryonic kidney 293) cells and showed that the ASC speck polymerization is independent of NEK7 in the context of this cell system. Probing the interfaces observed in the different, existing structural models of NLRP3 oligomers, we present evidence that the NEK7-independent, constitutively active NLRP3 inflammasome core in HEK293 cells may resemble a stacked-torus-like hexamer seen for NLRP3 lacking its PYD (pyrin domain).
细胞质免疫受体 NLRP3（核苷酸结合域、富含亮氨酸重复序列（LRR）和吡喃结构域（PYD）的蛋白 3）在响应微生物和危险信号时，寡聚形成一种称为炎性体的超分子复合物的核心。人们认为，NLRP3 必须与 NEK7（NIMA（不在有丝分裂基因 a）相关激酶 7）结合，才能形成功能性炎性体核心，诱导衔接蛋白 ASC（含 CARD（半胱氨酸天冬氨酸蛋白酶募集结构域）的凋亡相关斑点样蛋白）的聚合，这是 NLRP3 活性的标志。我们在改良的 HEK293（人胚肾 293）细胞中重建了 NLRP3 炎性体活性，并表明在这种细胞系统中，ASC 斑点聚合不依赖于 NEK7。探测在 NLRP3 寡聚体的不同现有结构模型中观察到的界面，我们提供的证据表明，在 HEK293 细胞中，NEK7 非依赖性、组成性激活的 NLRP3 炎性体核心可能类似于缺乏 PYD（吡喃结构域）的 NLRP3 所见的堆叠环六聚体。
