The Technion Rappaport Integrated Cancer Center (T-RICC), The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, 3109601, Israel.
The Smoler Proteomics Center, Faculty of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel.
Biochem Biophys Res Commun. 2021 Jun 18;558:224-230. doi: 10.1016/j.bbrc.2020.08.098. Epub 2020 Sep 12.
The NF-κB transcription factor is involved in inflammation and cell proliferation, survival, and transformation. It is a heterodimer made of p50 or p52 and a member of the Rel family of proteins. p50 and p52 are derived from limited ubiquitin- and proteasome-mediated proteolytic processing of the larger precursors p105 and p100, respectively. Both precursors can be either processed or completely degraded by the ubiquitin-proteasome system. Previous work in our laboratory identified KPC1 as a ubiquitin ligase that mediates processing of p105 to the p50 subunit. Overexpression of the ligase leads to increased level of p50 with a resultant marked tumor-suppressive effect. In the present study, we identify FBXO7, a known ubiquitin ligase that binds to p105 and ubiquitinates it, but surprisingly, leads to its accumulation and to that of p65 - the Rel partner of p50 - and to increased cell proliferation. Importantly, a ΔF-Box mutant of FBXO7 which is inactive has similar effects on accumulation of p105 and cell proliferation, strongly suggesting that p105 is a pseudo substrate of FBXO7.
NF-κB 转录因子参与炎症以及细胞的增殖、存活和转化。它是由 p50 或 p52 与 Rel 家族蛋白成员组成的异二聚体。p50 和 p52 分别来自较大前体 p105 和 p100 的有限泛素化和蛋白酶体介导的蛋白水解加工。前体 p105 和 p100 都可以被泛素蛋白酶体系统加工或完全降解。我们实验室之前的工作鉴定出 KPC1 是一种泛素连接酶，介导 p105 加工为 p50 亚基。该连接酶的过表达导致 p50 水平升高，从而产生显著的肿瘤抑制作用。在本研究中，我们鉴定出 FBXO7，一种已知与 p105 结合并使其泛素化的泛素连接酶，但令人惊讶的是，它导致 p105 及其与 p65（p50 的 Rel 伴侣）的积累以及细胞增殖增加。重要的是，FBXO7 的ΔF-Box 突变体（无活性）对 p105 的积累和细胞增殖具有相似的影响，这强烈表明 p105 是 FBXO7 的伪底物。
