Elevated NF-κB activity is a contributory factor in many haematological and solid malignancies. Nucleolar sequestration of NF-κB/RelA represses this elevated activity and mediates apoptosis of cancer cells. Here we set out to understand the mechanisms that control the nuclear/nucleolar distribution of RelA and other regulatory proteins, so that agents can be developed that specifically target these proteins to the organelle. We demonstrate that RelA accumulates in intra-nucleolar aggresomes in response to specific stresses. We also demonstrate that the autophagy receptor, SQSTM1/p62, accumulates alongside RelA in these nucleolar aggresomes. This accumulation is not a consequence of inhibited autophagy. Indeed, our data suggest nucleolar and autophagosomal accumulation of p62 are in active competition. We identify a conserved motif at the N-terminus of p62 that is essential for nucleoplasmic-to nucleolar transport of the protein. Furthermore, using a dominant negative mutant deleted for this nucleolar localisation signal (NoLS), we demonstrate a role for p62 in trafficking RelA and other aggresome-related proteins to nucleoli, to induce apoptosis. Together, these data identify a novel role for p62 in trafficking nuclear proteins to nucleolar aggresomes under conditions of cell stress, thus maintaining cellular homeostasis. They also provide invaluable information on the mechanisms that regulate the nuclear/nucleolar distribution of RelA that could be exploited for therapeutic purpose. Implications: The data open up avenues for the development of a unique class of therapeutic agents that act by targeting RelA and other aberrantly active proteins to nucleoli, thus killing cancer cells.

中文翻译：

---

自噬受体 SQSTM1/p62 在将 NF-κB/RelA 转运至核仁聚集体中的作用

NF-κB 活性升高是许多血液学和实体恶性肿瘤的一个促成因素。NF-κB/RelA 的核仁隔离抑制了这种升高的活性并介导了癌细胞的凋亡。在这里，我们着手了解控制 RelA 和其他调节蛋白的核/核仁分布的机制，以便可以开发出将这些蛋白质特异性靶向细胞器的试剂。我们证明 RelA 在响应特定压力时在核仁内聚集体中积累。我们还证明自噬受体 SQSTM1/p62 在这些核仁聚集体中与 RelA 一起积累。这种积累不是自噬受抑制的结果。事实上，我们的数据表明 p62 的核仁和自噬体积累正在积极竞争。我们在 p62 的 N 末端鉴定了一个保守的基序，这对于蛋白质从核质到核仁的转运至关重要。此外，使用为该核仁定位信号 (NoLS) 删除的显性负突变体，我们证明了 p62 在将 RelA 和其他聚集体相关蛋白运输到核仁中的作用，以诱导细胞凋亡。总之，这些数据确定了 p62 在细胞应激条件下将核蛋白运输到核仁聚集体中的新作用，从而维持细胞稳态。它们还提供了关于调节 RelA 核/核仁分布的机制的宝贵信息，可用于治疗目的。含义：