Regulating proteasome biogenesis in mammals: Transcriptional networks, assembly pathways, and disease connections

The ubiquitin–proteasome system (UPS) is the principal pathway for selective intracellular protein degradation and plays essential roles in proteome homeostasis, stress adaptation, immunity, and cellular remodeling. Proper proteasome function depends not only on catalytic activity but also on coordinated regulation of proteasome subunit expression, assembly, maturation, and adaptive remodeling. While early studies in budding yeast established the Rpn4-mediated proteasome stress response as a major mechanism linking proteasome demand to proteasome production, recent work has revealed that mammalian proteasome biogenesis is controlled by multilayered networks involving major regulators of proteasome gene expression, stress-responsive pathways, inflammatory signaling, metabolic adaptation, and tissue-specific programs. The NFE2L1 (Nrf1)-mediated proteasome recovery pathway is the best-characterized adaptive transcriptional mechanism, while increasing evidence indicates that proteasome gene promoters are regulated through combinatorial and context-dependent mechanisms rather than by a single regulatory element. Recent studies further suggest that subunit-selective regulators may contribute to mammalian proteasome gene expression through both coordinated and modular modes of transcriptional control. Human genetic studies have also highlighted the biological importance of proteasome biogenesis, linking defects in proteasome subunits and assembly factors to autoinflammatory disorders, neurodevelopmental abnormalities, and degenerative phenotypes. Together, these findings suggest that proteasome insufficiency can arise not only from impaired catalytic activity but also from dysregulation of proteasome biogenesis pathways. In this review, we summarize current understanding of proteasome biogenesis with a particular focus on transcriptional regulation, assembly pathways, adaptive remodeling, and disease mechanisms. We propose a framework in which proteasome biogenesis is viewed as an adaptive proteostasis network rather than a constitutive housekeeping process.