Nuclear proteins participate in diverse cellular processes, many of which are essential for cell survival and viability. To maintain optimal nuclear physiology, the cell employs the ubiquitin-proteasome system to eliminate damaged and misfolded proteins in the nucleus that could otherwise harm the cell. In this review, we highlight the current knowledge about the major ubiquitin-protein ligases involved in protein quality control degradation (PQCD) in the nucleus and how they orchestrate their functions to eliminate misfolded proteins in different nuclear subcompartments. Many human disorders are causally linked to protein misfolding in the nucleus, hence we discuss major concepts that still need to be clarified to better understand the basis of the nuclear misfolded proteins' toxic effects. Additionally, we touch upon potential strategies for manipulating nuclear PQCD pathways to ameliorate diseases associated with protein misfolding and aggregation in the nucleus.

The ubiquitin-mediated proteasomal degradation of misfolded proteins is generally thought to require Hsp70 chaperones, particularly Ssa1 and Ssa2 in yeast. This study reveals that Ssa1/Ssa2 are involved in the degradation of misfolded proteins in the yeast nucleus, but their degree of involvement varies depending on the misfolded nuclear protein.

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