Inserm, U1016, Institut Cochin, Paris, France.
CNRS, UMR8104, Paris, France.
Oncogene. 2021 Mar;40(12):2243-2257. doi: 10.1038/s41388-021-01704-w. Epub 2021 Mar 1.
Mdm2 antagonizes the tumor suppressor p53. Targeting the Mdm2-p53 interaction represents an attractive approach for the treatment of cancers with functional p53. Investigating mechanisms underlying Mdm2-p53 regulation is therefore important. The scaffold protein β-arrestin2 (β-arr2) regulates tumor suppressor p53 by counteracting Mdm2. β-arr2 nucleocytoplasmic shuttling displaces Mdm2 from the nucleus to the cytoplasm resulting in enhanced p53 signaling. β-arr2 is constitutively exported from the nucleus, via a nuclear export signal, but mechanisms regulating its nuclear entry are not completely elucidated. β-arr2 can be SUMOylated, but no information is available on how SUMO may regulate β-arr2 nucleocytoplasmic shuttling. While we found β-arr2 SUMOylation to be dispensable for nuclear import, we identified a non-covalent interaction between SUMO and β-arr2, via a SUMO interaction motif (SIM), that is required for β-arr2 cytonuclear trafficking. This SIM promotes association of β-arr2 with the multimolecular RanBP2/RanGAP1-SUMO nucleocytoplasmic transport hub that resides on the cytoplasmic filaments of the nuclear pore complex. Depletion of RanBP2/RanGAP1-SUMO levels result in defective β-arr2 nuclear entry. Mutation of the SIM inhibits β-arr2 nuclear import, its ability to delocalize Mdm2 from the nucleus to the cytoplasm and enhanced p53 signaling in lung and breast tumor cell lines. Thus, a β-arr2 SIM nuclear entry checkpoint, coupled with active β-arr2 nuclear export, regulates its cytonuclear trafficking function to control the Mdm2-p53 signaling axis.
Mdm2 拮抗肿瘤抑制因子 p53。靶向 Mdm2-p53 相互作用代表了治疗具有功能性 p53 的癌症的一种有吸引力的方法。因此，研究 Mdm2-p53 调节的机制非常重要。支架蛋白β-arrestin2（β-arr2）通过拮抗 Mdm2 来调节肿瘤抑制因子 p53。β-arr2 的核质穿梭会将 Mdm2 从细胞核排斥到细胞质中，从而增强 p53 信号。β-arr2 通过核输出信号从细胞核中持续输出，但调节其核内进入的机制尚未完全阐明。β-arr2 可以被 SUMO 化，但关于 SUMO 如何调节β-arr2 的核质穿梭尚无信息。虽然我们发现β-arr2 的 SUMO 化对于核内输入不是必需的，但我们发现 SUMO 与β-arr2 之间存在非共价相互作用，通过 SUMO 相互作用基序（SIM），这对于β-arr2 的细胞质核运输是必需的。该 SIM 促进β-arr2 与位于核孔复合体细胞质丝上的多分子 RanBP2/RanGAP1-SUMO 核质转运枢纽的关联。RanBP2/RanGAP1-SUMO 水平的耗尽会导致β-arr2 核内进入缺陷。SIM 的突变抑制了β-arr2 的核内输入，使其将 Mdm2 从细胞核重定位到细胞质的能力以及在肺和乳腺癌肿瘤细胞系中增强 p53 信号。因此，β-arr2 SIM 核内进入检查点，与β-arr2 的主动核内输出相结合，调节其细胞质核运输功能，以控制 Mdm2-p53 信号轴。
