Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA.
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA.
Cell. 2019 Apr 4;177(2):384-398.e11. doi: 10.1016/j.cell.2019.01.039. Epub 2019 Mar 7.
The signaling organelles of the innate immune system consist of oligomeric protein complexes known as supramolecular organizing centers (SMOCs). Examples of SMOCs include myddosomes and inflammasomes, which respectively induce transcription-dependent and -independent inflammatory responses. The common use of oligomeric structures as signaling platforms suggests multifunctionality, but each SMOC has a singular biochemically defined function. Here, we report that the myddosome is a multifunctional organizing center. In addition to promoting inflammatory transcription factor activation, the myddosome drives the rapid induction of glycolysis. We identify the kinase TBK1 as a myddosome component that promotes glycolysis, but not nuclear factor κB (NF-κB) activation. Synthetic immunology approaches further diversified SMOC activities, as we created interferon- or necroptosis-inducing myddosomes, inflammasomes that induce interferon responses instead of pyroptosis, and a SMOC-like nanomachine that induces interferon expression in response to a chemical ligand. These discoveries demonstrate the flexibility of immune signaling organelles, which permits the design of user-defined innate immune responses.
天然免疫系统的信号细胞器由寡聚蛋白复合物组成，称为超分子组织中心 (SMOC)。SMOC 的例子包括 MyD88 衔接子相关激酶 (myddosome) 和炎性小体，它们分别诱导依赖转录和非依赖转录的炎症反应。寡聚结构作为信号平台的常见用途表明其具有多功能性，但每个 SMOC 都具有独特的生化定义功能。在这里，我们报告了 MyD88 衔接子相关激酶 (myddosome) 是一种多功能组织中心。除了促进炎症转录因子的激活外，MyD88 衔接子相关激酶 (myddosome) 还能快速诱导糖酵解。我们确定激酶 TBK1 是 MyD88 衔接子相关激酶 (myddosome) 的一个组成部分，它能促进糖酵解，但不能促进核因子 κB (NF-κB) 的激活。合成免疫学方法进一步多样化了 SMOC 的活性，因为我们创建了能诱导干扰素或细胞坏死性凋亡的 MyD88 衔接子相关激酶 (myddosome)、能诱导干扰素反应而不是细胞焦亡的炎性小体，以及一种能在化学配体刺激下诱导干扰素表达的 SMOC 样纳米机器。这些发现表明，免疫信号细胞器具有灵活性，可以设计用户定义的先天免疫反应。
