Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105
J Immunol. 2020 Nov 15;205(10):2778-2785. doi: 10.4049/jimmunol.2000244. Epub 2020 Sep 28.
Mutations in , the gene encoding pyrin in humans, are associated with the autoinflammatory disorder familial Mediterranean fever. Pyrin is an innate sensor that assembles into an inflammasome complex in response to Rho-modifying toxins, including toxins A and B. Cell death pathways have been shown to intersect with and modulate inflammasome activation, thereby affecting host defense. Using bone marrow-derived macrophages and a murine model of peritonitis, we show in this study that receptor-interacting protein kinase (RIPK) 3 impacts pyrin inflammasome activation independent of its role in necroptosis. RIPK3 was instead required for transcriptional upregulation of through negative control of the mechanistic target of rapamycin (mTOR) pathway and independent of alterations in MAPK and NF-κB signaling. RIPK3 did not affect pyrin dephosphorylation associated with inflammasome activation. We further demonstrate that inhibition of mTOR was sufficient to promote expression and pyrin inflammasome activation, highlighting the cross-talk between the mTOR pathway and regulation of the pyrin inflammasome. Our study reveals a novel interaction between molecules involved in cell death and the mTOR pathway to regulate the pyrin inflammasome, which can be harnessed for therapeutic interventions.
在人类中，编码pyrin 的基因 的突变与自身炎症性疾病家族性地中海热有关。Pyrin 是一种先天传感器，它在响应 Rho 修饰毒素（包括 A 和 B 毒素）时组装成炎症小体复合物。已经表明细胞死亡途径与炎症小体激活相交，并调节其激活，从而影响宿主防御。在这项研究中，我们使用骨髓来源的巨噬细胞和腹膜炎的小鼠模型表明，受体相互作用蛋白激酶（RIPK）3 独立于其在坏死作用中的作用，影响 pyrin 炎症小体的激活。相反，RIPK3 通过负调控机械靶标雷帕霉素（mTOR）途径来上调 的转录，而不改变 MAPK 和 NF-κB 信号，从而需要 RIPK3。RIPK3 不影响与炎症小体激活相关的 pyrin 去磷酸化。我们进一步证明，抑制 mTOR 足以促进 表达和 pyrin 炎症小体激活，突出了 mTOR 途径和 pyrin 炎症小体调节之间的交叉对话。我们的研究揭示了参与细胞死亡的分子与 mTOR 途径之间的新相互作用，以调节 pyrin 炎症小体，这可以为治疗干预提供依据。
