Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA.
Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nat Cell Biol. 2018 May;20(5):586-596. doi: 10.1038/s41556-018-0084-5. Epub 2018 Apr 25.
Kelch-like protein 6 (KLHL6) is an uncharacterized gene mutated in diffuse large B-cell lymphoma (DLBCL). Here we report that KLHL6 assembles with cullin3 to form a functional cullin-RING ubiquitin ligase. Mutations in KLHL6 inhibit its ligase activity by disrupting the interaction with cullin3. Loss of KLHL6 favours DLBCL growth and survival both in vitro and in xenograft models. We further established that the mRNA decay factor roquin2 is a substrate of KLHL6. Degradation of roquin2 is dependent on B-cell receptor activation, and requires the integrity of the Tyr691 residue in roquin2 that is essential for its interaction with KLHL6. A non-degradable roquin2(Y691F) mutant requires its RNA-binding ability to phenocopy the effect of KLHL6 loss. Stabilization of roquin2 promotes mRNA decay of the tumour suppressor and NF-κB pathway inhibitor, tumour necrosis factor-α-inducible gene 3. Collectively, our findings uncover the tumour suppressing mechanism of KLHL6.
Kelch 样蛋白 6（KLHL6）是弥漫性大 B 细胞淋巴瘤（DLBCL）中突变的未鉴定基因。在这里，我们报告 KLHL6 与 cullin3 组装形成功能性 cullin-RING 泛素连接酶。KLHL6 中的突变通过破坏与 cullin3 的相互作用来抑制其连接酶活性。KLHL6 的缺失有利于体外和异种移植模型中 DLBCL 的生长和存活。我们进一步确定 mRNA 降解因子 roquin2 是 KLHL6 的底物。roquin2 的降解依赖于 B 细胞受体的激活，并且需要 roquin2 中 Tyr691 残基的完整性，该残基对于其与 KLHL6 的相互作用至关重要。不可降解的 roquin2(Y691F)突变体需要其 RNA 结合能力来模拟 KLHL6 缺失的效果。roquin2 的稳定化促进肿瘤抑制因子和 NF-κB 途径抑制剂肿瘤坏死因子-α诱导基因 3 的 mRNA 降解。总之，我们的发现揭示了 KLHL6 的肿瘤抑制机制。
