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.

P62/SQSTM1 is a multifunctional scaffold protein central to selective autophagy and, more recently, recognized as a regulator of ubiquitin–proteasome system-mediated degradation of intracellular proteins. Within phase-separated condensates, p62 has been shown to recruit and sequester the proteasome, yet the molecular basis for this interaction has remained largely unknown. Our previous study demonstrated that the ‘PB1’ domain (residues 1–123) of p62 is necessary for proteasome binding. However, this long stretch is also responsible for other functions of p62, such as condensate assembly and signal transduction. Thus, it was important to define more precisely the region responsible for interaction with the proteasome. In this study, we used systematic deletion variants of p62 and biochemical assays to delineate the minimal sequence within the PB1 domain responsible for proteasome binding. Our analyses revealed a small stretch of six amino acids (residues 84–89) that bind the proteasome and are distinct from the region responsible for condensate formation. Such a precise variant can serve as a useful tool to dissect how p62–proteasome interaction affects selective degradation and probably stress response, separating it from other p62 functions. Overall, this work advances our understanding of the structural determinants underlying p62’s dual role in autophagy and UPS regulation.

The ubiquitin–proteasome system (UPS) has been ‘traditionally’ described as a tightly regulated degradative network driven mainly by the specificity of its ubiquitin-conjugating enzymatic components. The proteasome on the other hand was thought to be a multi-subunit proteolytic complex that recognizes in a non-discriminatory manner ubiquitin-marked target substrates with less than a handful of exceptions. However, emerging evidence reveals that proteasome function is also dynamically regulated by multiple factors such as subunit composition and synthesis, post-translational modifications, and spatial localization which by itself it tightly regulated by the metabolic state of the cell. All these mechanisms add critical regulatory layers to protein homeostasis. This review highlights these newly evolving developments and discusses the pathogenic sequelae of their dysregulation.

The ubiquitin–proteasome system (UPS) has traditionally been described as a tightly regulated degradative network driven mainly by the specificity of its ubiquitin-conjugating enzymatic components. The 26S proteasome is the catalytic arm of the system that acts downstream to the conjugation machinery. For a long time, it has been considered to be a constitutive multi-subunit proteolytic complex that recognizes in a non-discriminatory manner ubiquitin-marked target substrates with less than a handful of exceptions. However, emerging evidence reveals that the 26S proteasome function is also dynamically regulated by multiple factors, such as subunit composition and synthesis, post-translational modifications, and spatial localization, all of which are tightly regulated by the metabolic and stress states of the cell. Importantly, dysregulation of these newly emerging regulatory mechanisms has pathogenic sequelae. These mechanisms fine-tune proteasome activity and expand its role as an active regulator of protein homeostasis rather than being a passive degradation machinery. Given the rapid expansion of these findings and their impact on our understanding of proteasome biology, an integrated overview of these regulatory mechanisms is timely.