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

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Original languageEnglish
JournalMolecular cancer research : MCR
Early online date23 Oct 2020
DOIs
Publication statusE-pub ahead of print - 23 Oct 2020

Abstract

Elevated NF-kB activity is a contributory factor in many haematological and solid
malignancies. Nucleolar sequestration of NF-kB/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.

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