A role for the autophagic receptor, SQSTM1/p62, in trafficking NF-kB/RelA to nucleolar aggresomes

Abstract

Elevated NF-{kappa}B activity is a contributory factor in many haematological and solid malignancies. Nucleolar sequestration of NF-{kappa}B/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. Together, these data identify a novel role for p62 in trafficking nuclear proteins to nucleolar aggresomes under conditions of cell stress, thus maintaining nuclear proteostasis. They also provide invaluable information on the mechanisms that regulate the nuclear/nucleolar distribution of RelA that could be exploited for therapeutic purpose. SignificanceAberrant NF-{kappa}B activity drives many of the hallmarks of cancer and plays a key role in cancer progression. Nucleolar sequestration of NF-{kappa}B/RelA is one mechanism that switches off this activity and induces the death of cancer cells. Here we define a novel role for the autophagy receptor, SQSTM1/p62 in transport of nucleoplasmic NF-{kappa}B/RelA to nucleoli. Identification of this new trafficking mechanism opens up avenues for the development of a unique class of therapeutic agents that transport RelA and other cancer regulatory proteins to this organelle.