Abstract
The ubiquitin-proteasome system (UPS) is essential for maintaining cellular proteostasis by selective proteasomal degradation of ubiquitinated proteins. Proper function of the UPS ensures turnover of proteins that have completed their role and removal of damaged proteins. Recent studies have identified p62/Sequestosome-1 as a key modulator of UPS efficiency, particularly through its ability to form dynamic, membraneless condensates via liquid-liquid phase separation. Within the nucleus, these structures recruit and concentrate components of the UPS, including its proteolytic arm - the 26S proteasome and ubiquitinated substrates. This organization enhances substrate recognition and degradation efficiency. Nuclear p62 condensates play an essential role in controlling the turnover of oncogenic proteins. Specifically, they facilitate the proteasomal degradation of the transcription factor c-Myc and prevent its nuclear accumulation by recruiting both c-Myc and its E3 ligase complex SCFFbxw7. Additionally, nuclear p62 condensates contribute to the maintenance of promyelocytic leukemia (PML) nuclear bodies and protect them from stress-induced disassembly by stabilizing the PML protein through sequestration and subsequent degradation of RING Finger Protein 4 (RNF4) - its major E3 ligase. Under stress conditions such as oxidative stress, heat shock, or DNA damage, p62 nuclear condensates rapidly assemble and recruit molecular chaperones and ubiquitin ligases, thereby promoting the clearance of misfolded and damaged proteins. Loss of nuclear p62 or disruption of its condensate-forming domains affects UPS function and compromises proteostasis. These findings highlight the role of p62 condensates in coordinating nuclear protein quality control and protecting cells from proteotoxic and oncogenic stress.