Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany.
Biotechnology Institute Thurgauhttps://ror.org/0546hnb39 at the University of Konstanz, Kreuzlingen, Switzerland.
Life Sci Alliance. 2023 May 15;6(8). doi: 10.26508/lsa.202201463. Print 2023 Aug.
The interaction of the 19S regulatory particle of the 26S proteasome with ubiquitylated proteins leads to gate opening of the 20S core particle and increases its proteolytic activity by binding of the ubiquitin chain to the inhibitory deubiquitylation enzyme USP14 on the 19S regulatory subunit RPN1. Covalent modification of proteins with the cytokine inducible ubiquitin-like modifier FAT10 is an alternative signal for proteasomal degradation. Here, we report that FAT10 and its interaction partner NUB1L facilitate the gate opening of the 20S proteasome in an ubiquitin- and USP14-independent manner. We also show that FAT10 is capable to activate all peptidolytic activities of the 26S proteasome, however only together with NUB1L, by binding to the UBA domains of NUB1L and thereby interfering with NUB1L dimerization. The binding of FAT10 to NUB1L leads to an increased affinity of NUB1L for the subunit RPN1. In conclusion, the herein described cooperation of FAT10 and NUB1L is a substrate-induced mechanism to activate the 26S proteasome.
26S 蛋白酶体的 19S 调节颗粒与泛素化蛋白的相互作用导致 20S 核心颗粒的门打开，并通过将泛素链结合到 19S 调节亚基 RPN1 上的抑制去泛素化酶 USP14 来增加其蛋白水解活性。细胞因子诱导的泛素样修饰物 FAT10 对蛋白质的共价修饰是蛋白酶体降解的另一种信号。在这里，我们报告 FAT10 及其相互作用伙伴 NUB1L 以泛素和 USP14 非依赖性方式促进 20S 蛋白酶体的门打开。我们还表明，FAT10 能够通过与 NUB1L 的 UBA 结构域结合并由此干扰 NUB1L 二聚化，激活 26S 蛋白酶体的所有肽酶活性，但仅与 NUB1L 一起。FAT10 与 NUB1L 的结合导致 NUB1L 对亚基 RPN1 的亲和力增加。总之，本文描述的 FAT10 和 NUB1L 的合作是一种底物诱导的机制，可激活 26S 蛋白酶体。
