美国波士顿儿童医院Hao Wu和美国密歇根大学Yongqing Li研究组的合作取得一项新进展。他们揭示了组蛋白脱乙酰基酶6（HDAC6）介导NLRP3和吡喃炎症小体激活的聚集体样机制。这一研究成果于2020年9月18日发表在《科学》杂志上。
他们显示了在微管组织中心（MTOC）发生了核苷酸结合结构域、富含亮氨酸的重复序列以及含吡喃结构域的蛋白3（NLRP3）和由吡喃介导的炎症小体装配，半胱氨酸蛋白酶激活和白介素1β（IL-1β）转化。此外，在体外和小鼠体内实验表明，这些炎症小体的微管运输和组装中，动力蛋白适配器HDAC6都是必不可少的。
因为HDAC6可以将泛泛素化的病理性聚集体转运至MTOC以形成聚集体和自噬体降解，所以其在NLRP3和吡喃炎症小体激活中的作用也提供了通过自噬下调这些炎症小体的内在机制。这项工作表明生理和病理聚集体的形成之间出乎意料的一致。
据悉，炎性小体是超分子复合物，在免疫监视中起关键作用。这是通过激活炎症性半胱氨酸蛋白酶来实现的，该酶导致IL-1β的蛋白水解成熟和细胞凋亡。
附：英文原文
Title: HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation
Author: Venkat Giri Magupalli, Roberto Negro, Yuzi Tian, Arthur V. Hauenstein, Giuseppe Di Caprio, Wesley Skillern, Qiufang Deng, Pontus Orning, Hasan B. Alam, Zoltan Maliga, Humayun Sharif, Jun Jacob Hu, Charles L. Evavold, Jonathan C. Kagan, Florian I. Schmidt, Katherine A. Fitzgerald, Tom Kirchhausen, Yongqing Li, Hao Wu
Issue&Volume: 2020/09/18
Abstract: 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.
DOI: 10.1126/science.aas8995
Source: https://science.sciencemag.org/content/369/6510/eaas8995