Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Science. 2020 Sep 18;369(6510). doi: 10.1126/science.aas8995.
Inflammasomes are supramolecular complexes that play key roles in immune surveillance. This is accomplished by the activation of inflammatory caspases, which leads to the proteolytic maturation of interleukin 1β (IL-1β) and pyroptosis. Here, we show that nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3)- and pyrin-mediated inflammasome assembly, caspase activation, and IL-1β conversion occur at the microtubule-organizing center (MTOC). Furthermore, the dynein adapter histone deacetylase 6 (HDAC6) is indispensable for the microtubule transport and assembly of these inflammasomes both in vitro and in mice. Because HDAC6 can transport ubiquitinated pathological aggregates to the MTOC for aggresome formation and autophagosomal degradation, its role in NLRP3 and pyrin inflammasome activation also provides an inherent mechanism for the down-regulation of these inflammasomes by autophagy. This work suggests an unexpected parallel between the formation of physiological and pathological aggregates.
炎症小体是在免疫监视中发挥关键作用的超分子复合物。这是通过炎性半胱天冬酶的激活来实现的，这导致白细胞介素 1β（IL-1β）和细胞焦亡的蛋白水解成熟。在这里，我们表明核苷酸结合域、富含亮氨酸重复和吡喃结构域蛋白 3（NLRP3）和吡喃介导的炎症小体组装、半胱天冬酶激活和 IL-1β转化发生在微管组织中心（MTOC）。此外，动力蛋白接头组蛋白去乙酰化酶 6（HDAC6）对于这些炎症小体在体外和在小鼠中的微管运输和组装都是必不可少的。因为 HDAC6 可以将泛素化的病理性聚集体运输到 MTOC 以形成聚集体并进行自噬体降解，所以它在 NLRP3 和吡喃炎症小体激活中的作用也为自噬对这些炎症小体的下调提供了内在机制。这项工作表明生理和病理性聚集体的形成之间存在一种意想不到的平行关系。
