Kliza Katarzyna W, Song Wei, Pinzuti Irene, Schaubeck Simone, Kunzelmann Simone, Kuntin David, Fornili Arianna, Pandini Alessandro, Hofmann Kay, Garnett James A, Stieglitz Benjamin, Husnjak Koraljka
Institute of Biochemistry II, Goethe University School of Medicine, Frankfurt (Main), Germany.
Max Planck Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227, Dortmund, Germany.
Cell Death Discov. 2024 Apr 20;10(1):183. doi: 10.1038/s41420-024-01913-8.
Signalling through TNFR1 modulates proinflammatory gene transcription and programmed cell death, and its impairment causes autoimmune diseases and cancer. NEDD4-binding protein 1 (N4BP1) is a critical suppressor of proinflammatory cytokine production that acts as a regulator of innate immune signalling and inflammation. However, our current understanding about the molecular properties that enable N4BP1 to exert its suppressive potential remain limited. Here, we show that N4BP1 is a novel linear ubiquitin reader that negatively regulates NFκB signalling by its unique dimerization-dependent ubiquitin-binding module that we named LUBIN. Dimeric N4BP1 strategically positions two non-selective ubiquitin-binding domains to ensure preferential recognition of linear ubiquitin. Under proinflammatory conditions, N4BP1 is recruited to the nascent TNFR1 signalling complex, where it regulates duration of proinflammatory signalling in LUBIN-dependent manner. N4BP1 deficiency accelerates TNFα-induced cell death by increasing complex II assembly. Under proapoptotic conditions, caspase-8 mediates proteolytic processing of N4BP1, resulting in rapid degradation of N4BP1 by the 26 S proteasome, and acceleration of apoptosis. In summary, our findings demonstrate that N4BP1 dimerization creates a novel type of ubiquitin reader that selectively recognises linear ubiquitin which enables the timely and coordinated regulation of TNFR1-mediated inflammation and cell death.
通过肿瘤坏死因子受体1（TNFR1）发出的信号调节促炎基因转录和程序性细胞死亡，其功能受损会导致自身免疫性疾病和癌症。NEDD4结合蛋白1（N4BP1）是促炎细胞因子产生的关键抑制因子，作为先天免疫信号和炎症的调节因子发挥作用。然而，我们目前对使N4BP1发挥其抑制潜能的分子特性的了解仍然有限。在这里，我们表明N4BP1是一种新型的线性泛素阅读器，它通过其独特的依赖二聚化的泛素结合模块（我们命名为LUBIN）对核因子κB（NFκB）信号进行负调控。二聚体N4BP1策略性地定位两个非选择性泛素结合结构域，以确保对线性泛素的优先识别。在促炎条件下，N4BP1被招募到新生的TNFR1信号复合物中，在那里它以依赖LUBIN的方式调节促炎信号的持续时间。N4BP1缺乏通过增加复合物II的组装加速肿瘤坏死因子α（TNFα）诱导的细胞死亡。在促凋亡条件下，半胱天冬酶-8介导N4BP1的蛋白水解加工，导致N4BP1被26S蛋白酶体快速降解，并加速细胞凋亡。总之，我们的研究结果表明，N4BP1二聚化产生了一种新型的泛素阅读器，它选择性地识别线性泛素，从而能够及时、协调地调节TNFR1介导的炎症和细胞死亡。
