Subcellular localization of the deubiquitinating enzyme BAP1 is deterministic for its tumor suppressor activity. While the monoubiquitination of BAP1 by an atypical E2/E3-conjugated enzyme UBE2O and BAP1 auto-deubiquitination are known to regulate its nuclear localization, the molecular mechanism by which BAP1 is imported into the nucleus has remained elusive. Here, we demonstrated that transportin-1 (TNPO1, also known as Karyopherin β2 or Kapβ2) targets an atypical C-terminal proline-tyrosine nuclear localization signal (PY-NLS) motif of BAP1 and serves as the primary nuclear transporter of BAP1 to achieve its nuclear import. TNPO1 binding dissociates dimeric BAP1 and sequesters the monoubiquitination sites flanking the PY-NLS of BAP1 to counteract the function of UBE2O that retains BAP1 in the cytosol. Our findings shed light on how TNPO1 regulates the nuclear import, self-association, and monoubiquitination of BAP1 pertinent to oncogenesis.

中文翻译：

---

肿瘤抑制因子 BAP1 核输入受转运蛋白 1 控制

去泛素化酶 BAP1 的亚细胞定位对其肿瘤抑制活性具有决定性作用。虽然已知非典型 E2/E3 缀合酶 UBE2O 对 BAP1 的单泛素化和 BAP1 自动去泛素化可调节其核定位，但 BAP1 导入细胞核的分子机制仍不清楚。在这里，我们证明了转运蛋白-1（TNPO1，也称为核转运蛋白β2或Kapβ2）靶向BAP1的非典型C端脯氨酸-酪氨酸核定位信号（PY-NLS）基序，并作为BAP1的主要核转运蛋白来实现它的核进口。TNPO1 结合解离二聚体 BAP1 并隔离 BAP1 PY-NLS 侧翼的单泛素化位点，以抵消 UBE2O 将 BAP1 保留在细胞质中的功能。我们的研究结果揭示了 TNPO1 如何调节与肿瘤发生相关的 BAP1 的核输入、自缔合和单泛素化。