FBXO42 facilitates Notch signaling activation and global chromatin relaxation by promoting K63-linked polyubiquitination of RBPJ.
FBXO42 facilitates Notch signaling activation and global chromatin relaxation by promoting K63-linked polyubiquitination of RBPJ.
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FBXO42 通过促进 RBPJ K63 连接的多聚泛素化来促进 Notch 信号激活和整体染色质松弛
DOI：
10.1126/sciadv.abq4831
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发表时间：
2022-09-23
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
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作者：
Notch-RBPJ（免疫球蛋白κ J区的重组信号结合蛋白）信号通路的失调已被发现与包括癌症在内的各种人类疾病相关;然而，这一关键信号通路如何通过其相互作用物和修饰进行微调仍然在很大程度上未知。在这项研究中，使用蛋白质组学方法，我们确定了F-box only蛋白42（FBXO 42）作为以前未鉴定的RBPJ相互作用。FBXO 42通过赖氨酸-63键促进RBPJ在赖氨酸-175上的多聚泛素化，这增强了RBPJ与染色质重塑复合物的结合并诱导了整体染色质松弛。基因耗竭FBXO 42或靶向其E3连接酶活性的E3受体可在体内减弱Notch信号相关的白血病发展。总之，我们的研究结果不仅揭示了FBXO 42通过调节RBPJ依赖性全局染色质景观变化作为Notch途径的关键调节因子，而且还为Notch途径治疗白血病提供了深入见解。FBXO 42促进RBPJ K63连接的泛素化和全局染色质景观变化。
Dysregulation of the Notch–RBPJ (recombination signal-binding protein of immunoglobulin kappa J region) signaling pathway has been found associated with various human diseases including cancers; however, precisely how this key signaling pathway is fine-tuned via its interactors and modifications is still largely unknown. In this study, using a proteomic approach, we identified F-box only protein 42 (FBXO42) as a previously unidentified RBPJ interactor. FBXO42 promotes RBPJ polyubiquitination on lysine-175 via lysine-63 linkage, which enhances the association of RBPJ with chromatin remodeling complexes and induces a global chromatin relaxation. Genetically depleting FBXO42 or pharmacologically targeting its E3 ligase activity attenuates the Notch signaling–related leukemia development in vivo. Together, our findings not only revealed FBXO42 as a critical regulator of the Notch pathway by modulating RBPJ-dependent global chromatin landscape changes but also provided insights into the therapeutic intervention of the Notch pathway for leukemia treatment. FBXO42 promotes RBPJ K63-linked ubiquitination and global chromatin landscape changes.
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影响因子：
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Gomez-Lamarca MJ;Falo-Sanjuan J;Stojnic R;Abdul Rehman S;Muresan L;Jones ML;Pillidge Z;Cerda-Moya G;Yuan Z;Baloul S;Valenti P;Bystricky K;Payre F;O'Holleran K;Kovall R;Bray SJ
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通讯作者：
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DOI：
10.1083/jcb.202009167
发表时间：
2021-02-01
期刊：
The Journal of cell biology
影响因子：
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作者：
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影响因子：
16
作者：
Hass MR;Liow HH;Chen X;Sharma A;Inoue YU;Inoue T;Reeb A;Martens A;Fulbright M;Raju S;Stevens M;Boyle S;Park JS;Weirauch MT;Brent MR;Kopan R
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DOI：
10.1074/mcp.m111.014050
发表时间：
2012-03
期刊：
Molecular & cellular proteomics : MCP
影响因子：
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Geiger T;Wehner A;Schaab C;Cox J;Mann M
通讯作者：
Mann M