Regulation of the localisation and function of the oncogene LYRIC/AEG‐1 by ubiquitination at K486 and K491

The pivotal role of LYRIC/AEG‐1 in malignant transformation, tumourigenesis and chemo‐resistance has previously been demonstrated in different cell types and sub‐cellular compartments. The localisation of LYRIC/AEG‐1 appears crucial to its function and is regulated by three lysine‐rich nuclear localisation signal regions, one of which was previously demonstrated to be modified by ubiquitin. Here we show that mutation of LYRIC/AEG‐1 at K486 and K491 results in a loss of ubiquitination. A K486/491R double mutant that is incapable of ubiquitination shows reduced binding to the NFκB subunit p65 or importin‐β resulting in a distinctive peri‐nuclear localisation of LYRIC/AEG‐1. We also provide evidence to suggest that TOPORS, an E3 ligase that also regulates p53 modification may be responsible for LYRIC/AEG‐1 ubiquitin modification. Overall we demonstrate that specific sites of LYRIC/AEG‐1 ubiquitination are essential for regulating LYRIC/AEG‐1 localisation and functionally interacting proteins.