A nuclear protein quality control system for elimination of nucleolus-related inclusions

The identification of pathways that control elimination of protein inclusions is essential to understand the cellular response to proteotoxicity, particularly in the nuclear compartment, for which our knowledge is limited. We report that stress-induced nuclear inclusions related to the nucleolus are eliminated upon stress alleviation during the recovery period. This process is independent of autophagy/lysosome and CRM1-mediated nuclear export pathways, but strictly depends on the ubiquitin-activating E1 enzyme, UBA1, and on nuclear proteasomes that are recruited into the formed inclusions. UBA1 activity is essential only for the recovery process but dispensable for nuclear inclusion formation. Furthermore, the E3 ligase HUWE1 and HSP70 are components of the ubiquitin/chaperone systems that promote inclusion elimination. The recovery process also requires RNA Pol I-dependent production of the lncRNA IGS₄₂ during stress. IGS₄₂ localises within the formed inclusions and promotes their elimination by preserving the mobility of resident proteins. These findings reveal a protein quality control system that operates within the nucleus for the elimination of stress-induced nucleolus-related inclusions.