Deep inside every mammalian cell, a molecular machine works around the clock to shred damaged, misfolded, and obsolete proteins. This machine, the proteasome, is the destructive heart of the ubiquitin–proteasome system, the principal pathway by which cells selectively degrade their own proteins. Without it, proteome balance collapses, stress responses fail, immunity falters, and the constant remodeling that keeps tissues healthy grinds to a halt. Yet for decades, most research focused on what the proteasome does rather than on how cells actually build it. A new review published in Cellular and Molecular Life Sciences by Jun Hamazaki, Masaya Suzuki, and Shigeo Murata of the University of Tokyo argues that this focus has been too narrow, and that the construction of the proteasome itself is a tightly regulated, adaptive process with profound implications for human disease.
The central claim of the review is provocative: proteasome biogenesis should be understood not as a constitutive housekeeping activity that hums along at a fixed rate, but as an adaptive proteostasis network that responds dynamically to demand. When the cell faces heat shock, oxidative stress, inflammatory signals, or metabolic shifts, its need for protein degradation changes dramatically. The cell must therefore adjust not only the catalytic activity of existing proteasomes but also the expression of proteasome subunit genes, the assembly of new particles, and the maturation of immature complexes into fully functional enzymes. Failure at any of these steps can produce what the authors call proteasome insufficiency, a state in which the cell’s degradative capacity falls short of its needs even when the proteasomes it does possess are perfectly functional.
Some of the foundational insights into this problem came not from mammals but from budding yeast. Early studies in yeast established the Rpn4-mediated proteasome stress response, a feedback loop in which the transcription factor Rpn4 activates the suite of genes encoding proteasome subunits whenever proteasome function is compromised. Rpn4 itself is degraded by the proteasome, creating an elegant self-balancing circuit: when proteasome activity drops, Rpn4 accumulates, drives subunit gene expression, and proteasome production rises until excess capacity destroys Rpn4 again. This yeast work provided the conceptual template for thinking about proteasome demand as a signal that directly controls proteasome supply. The new review emphasizes, however, that mammalian cells have evolved far more elaborate and layered versions of this logic.
The best-characterized adaptive mechanism in mammals is the NFE2L1 pathway, also known as Nrf1. NFE2L1 is a transcription factor that resides at the endoplasmic reticulum membrane and is normally continuously degraded by the proteasome in a process that involves its extraction from the membrane and destruction. When proteasome activity is inhibited or overwhelmed, NFE2L1 escapes degradation, is processed, and translocates to the nucleus, where it switches on the genes encoding proteasome subunits and assembly factors. This NFE2L1-mediated proteasome recovery pathway is the mammalian counterpart of the yeast Rpn4 circuit, and it has been shown to be essential for cells to rebound from proteotoxic stress. The review positions NFE2L1 as the anchor of our current understanding, while stressing that it is far from the whole story.
One of the most important recent conceptual shifts highlighted in the review concerns how proteasome gene promoters are actually controlled. Rather than being governed by a single regulatory element or a master switch, proteasome gene promoters appear to be regulated through combinatorial and context-dependent mechanisms. Multiple transcription factors, co-activators, and chromatin states converge on these promoters in ways that vary by cell type, developmental stage, and environmental condition. This combinatorial architecture explains a puzzling observation: different proteasome subunit genes can be regulated independently of one another, even though their protein products must ultimately be produced in roughly stoichiometric amounts to assemble a complete proteasome.
That puzzle points to what the authors describe as subunit-selective regulation. Recent studies suggest that individual regulators may act on specific subsets of proteasome genes, contributing to mammalian proteasome gene expression through both coordinated and modular modes of transcriptional control. In the coordinated mode, a regulator boosts many or all subunit genes together, scaling overall proteasome capacity upward or downward. In the modular mode, a regulator adjusts only particular subunits or assembly factors, potentially fine-tuning the composition of the proteasome population or relieving a bottleneck at a specific assembly step. This layered system allows mammalian cells to remodel their proteasome repertoire with remarkable precision, tailoring the degradative machinery to the particular demands of a neuron, an immune cell, a muscle fiber, or a dividing cancer cell.
Beyond transcription, the review surveys the assembly pathways themselves. Building a proteasome is an intricate engineering feat: the 20S catalytic core is a barrel-shaped complex of 28 subunits arranged in four stacked rings, and it must be assembled with the help of dedicated chaperones that guide ring formation, prevent premature activation, and coordinate the attachment of the 19S regulatory particles that recognize ubiquitinated substrates. Assembly factors act transiently, dissociating once their job is done, and their availability can limit the rate of proteasome production. The maturation process involves ordered steps of incorporation, processing, and activation, and disruptions in any of these steps can leave cells with a deficit of functional particles even when subunit production is normal.
The disease connections emerging from this field are among the most striking findings summarized in the review. Human genetic studies have linked defects in proteasome subunits and assembly factors to a growing list of disorders, including autoinflammatory conditions, neurodevelopmental abnormalities, and degenerative phenotypes. These are not simply diseases of proteasome catalysis; they are diseases of proteasome construction and regulation. Mutations in assembly factors can impair the efficiency with which subunits are assembled into mature particles, while mutations affecting transcriptional regulation can blunt the cell’s ability to scale proteasome production in response to stress. The review’s framework makes sense of this clinical spectrum: proteasome insufficiency can arise at multiple points along the biogenesis pipeline, and the tissue-specific consequences reflect the varying proteostatic demands of different cell types.
This perspective also reframes how scientists should think about therapeutic intervention. Proteasome inhibitors such as bortezomib are already mainstays in cancer therapy, exploiting the dependence of malignant cells on proteasome function. But if many diseases stem from inadequate proteasome biogenesis rather than inadequate catalytic activity, then strategies that boost the assembly and production of proteasomes, for example by modulating NFE2L1 signaling or the newly identified subunit-selective regulators, could offer a fundamentally different therapeutic approach. Enhancing the cell’s own capacity to build more proteasomes might ameliorate proteotoxic stress in neurodegenerative contexts, while dampening biogenesis could sensitize tumor cells that rely on high proteasome throughput. Realizing these possibilities will require a much more complete map of the transcriptional networks and assembly pathways that the review begins to assemble.
What emerges from the synthesis by Hamazaki, Suzuki, and Murata is a vision of the proteasome as anything but a static piece of cellular infrastructure. It is a machine whose very existence is continuously negotiated between supply and demand, tuned by stress sensors, inflammatory signals, metabolic state, and tissue-specific programs. The authors propose that the field should formally adopt the view of proteasome biogenesis as an adaptive proteostasis network, a shift that places construction and regulation of the degradative machinery on equal footing with its catalytic function. As human genetics continues to expose the consequences of biogenesis defects, and as molecular studies continue to uncover the combinatorial logic of proteasome gene regulation, this framework is likely to guide both basic discovery and drug development for years to come. The humble protein shredder, it turns out, is one of the most sophisticatedly regulated machines in the cell, and learning how cells build it may prove as important as learning what it destroys.
Subject of Research: Regulation of mammalian proteasome biogenesis through transcriptional networks, assembly pathways, and adaptive proteostasis
Article Title: Regulating proteasome biogenesis in mammals: Transcriptional networks, assembly pathways, and disease connections
Article References: Hamazaki, J., Suzuki, M., & Murata, S. (2026). Regulating proteasome biogenesis in mammals: Transcriptional networks, assembly pathways, and disease connections. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06463-z
Image Credits: AI Generated
DOI: 10.1007/s00018-026-06463-z
Keywords: proteasome, ubiquitin-proteasome system, proteostasis, NFE2L1, Nrf1, transcription factors, protein degradation, assembly factors, stress response, proteasome insufficiency, gene regulation, proteasome-associated diseases
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Juliet Wilcox. (September 30, 2026). How Cells Build Their Protein Shredder: New Rules of Proteasome Biogenesis. Scienmag. https://scienmag.com/how-cells-build-their-protein-shredder-new-rules-of-proteasome-biogenesis/
Juliet Wilcox. “How Cells Build Their Protein Shredder: New Rules of Proteasome Biogenesis.” Scienmag, 30 September 2026, https://scienmag.com/how-cells-build-their-protein-shredder-new-rules-of-proteasome-biogenesis/. Accessed 30 September 2026.
Juliet Wilcox. “How Cells Build Their Protein Shredder: New Rules of Proteasome Biogenesis.” Scienmag. September 30, 2026. https://scienmag.com/how-cells-build-their-protein-shredder-new-rules-of-proteasome-biogenesis/
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