Biologists have spent decades mapping how cells police their proteins. Chaperones refold misfolded chains, the proteasome shreds irreparable ones, and autophagy devours bulky aggregates. DNA repair pathways similarly guard the genome. But glycogen, a polymer of glucose assembled by glycogen synthase and sculpted by branching enzyme, has lacked an obvious surveillance mechanism. That gap matters clinically. In adults, aberrant, poorly branched glycogen builds up as polyglucosan bodies in disorders such as adult polyglucosan body disease, a condition caused by mutations in the branching enzyme gene GBE1 that can produce progressive weakness, numbness and neurogenic bladder. Until now, no one had identified a cellular machine that actively detects and removes these defective polymers before they crystallize into disease.

The Cambridge team began with genetics. Mice engineered to lack the ligase activity of RNF213, an enormous E3 ubiquitin ligase previously implicated in Moyamoya disease, a rare cerebrovascular disorder, accumulated polyglucosan in specific brain regions: the cerebellum, the pons and the hippocampus. That pattern of accumulation pointed to a protective role in astrocytes, the star-shaped support cells that stockpile much of the brain’s glycogen. The inference was striking. If removing RNF213’s enzymatic activity caused polyglucosan to pile up, then RNF213’s normal job might be to recognize aberrant glycogen and mark it for destruction, much as E3 ligases mark damaged proteins.

To test that idea directly, the researchers built a cell-based system in which cells manufacture polyglucosan, the pathological, sparsely branched form of glycogen. In these cells, RNF213 selectively attached ubiquitin to the abnormal polymer while leaving healthy, well-branched glycogen untouched. That selectivity is the crux of the discovery. Quality control is only useful if it distinguishes good from bad, and here the enzyme appeared to do exactly that, reading the structural state of a carbohydrate granule and tagging only the defective version. The tagged polyglucosan was then engulfed by autophagosomes, the cell’s membrane-bound disposal vesicles, in a process the authors describe as autophagy of ubiquitylated aberrant glycogen.

How does a protein enzyme read the architecture of a sugar polymer? Cryo-electron microscopy provided the answer. Wanda Kukulski’s group at the University of Bern joined the effort to solve the structure of RNF213 bound to maltoheptaose, a linear seven-glucose fragment derived from glycogen. The images revealed that RNF213 carries a carbohydrate-binding module, CBM20, that grips linear oligosaccharides. This detail matters because normal glycogen is densely branched, studded with short side chains, whereas polyglucosan is comparatively linear and sparse. The CBM20 domain, the structure implies, acts as a molecular ruler that prefers the exposed linear stretches characteristic of aberrant glycogen.

The structural work also explained a paradox. When the researchers mutated the carbohydrate-binding surface of CBM20, RNF213 did not lose its activity; it gained it, promiscuously ubiquitylating even physiological glycogen. In other words, the binding domain normally restrains the enzyme, preventing it from attacking healthy glycogen and licensing activity only when the polymer presents the right structural cues. Disrupting that restraint converts a precise quality control factor into a blunt instrument. This regulatory logic, in which substrate recognition gates catalytic output, echoes themes from protein quality control but is here applied to a branched carbohydrate, a conceptual first.

Ubiquitylation is only the first step of disposal. The study traced what happens next through epistasis analysis, which places genes in a pathway by testing how mutations combine. RNF213 acts upstream of LUBAC, a linear ubiquitin chain assembly complex, suggesting a hierarchy in which one E3 ligase initiates tagging and a second elaborates the mark. The resulting ubiquitin coat on polyglucosan then recruits autophagy receptors, including SQSTM1, also known as p62, TAX1BP1 and optineurin. These adaptor proteins physically link the tagged cargo to the autophagy machinery, triggering uptake into autophagosomes and eventual degradation. The network implies that glycogen surveillance, like protein surveillance, is a multi-layered system with division of labor among several enzymes.

The discovery also reframes RNF213 itself. The gene has attracted intense clinical interest because loss-of-function variants cause Moyamoya disease, and the protein’s ligase activity has been linked to lipid droplet biology and innate immunity. Adding glycogen quality control to its portfolio suggests that RNF213 is a broad-spectrum surveyor of cytoplasmic polymers, and it raises the question of whether some Moyamoya pathology might involve glycogen mishandling in brain cells, a possibility the study does not directly establish but which now invites investigation. It also broadens the emerging concept of non-protein ubiquitylation, in which ubiquitin marks lipids and carbohydrates, into a central pillar of cellular housekeeping.

For medicine, the implications are tantalizing but early. Adult polyglucosan body disease and related glycogen storage disorders currently lack therapies that address the root problem of insoluble polymer accumulation. If the RNF213 pathway can be understood well enough to enhance, perhaps by stabilizing the enzyme’s activity or boosting the autophagy receptors it engages, cells might in principle be taught to clear polyglucosan before it accumulates. The mouse data showing region-specific polyglucosan buildup in the absence of RNF213 ligase activity provide a model for testing such strategies. Caution is warranted: the work identifies a mechanism, not a treatment, and translating ubiquitin biology into drugs has historically proven difficult.

Scientifically, the study’s deepest significance may be conceptual. Quality control, biologists now realize, is not a protein-only affair. DNA, RNA, lipids and now glycogen all fall under the ubiquitin system’s jurisdiction, each with dedicated sensors and disposal routes. The Cambridge and Bern teams have shown that even a humble energy store is inspected, tagged and recycled with the same molecular rigor applied to a misfolded enzyme. Cells, it turns out, do not merely fill their glycogen granules and forget them. They watch them, and when the branching goes wrong, they call in RNF213.

Subject of Research: Ubiquitin-dependent quality control of glycogen by the E3 ligase RNF213

Article Title: Quality control of glycogen through direct ubiquitylation by RNF213

Article References: Yip, M. C. J., Naydenova, K., Otten, E. G., Heatley, A., Moe, A., Anton, L., de los Reyes-Ramírez, L., Jolin, H. E., Langevin, F., Wiacek, M., Franco, C., Bertolotti, A., Kukulski, W., McKenzie, A. N. J., & Randow, F. (2026). Quality control of glycogen through direct ubiquitylation by RNF213. Nature. https://doi.org/10.1038/s41586-026-11139-6

Image Credits: AI Generated

DOI: 10.1038/s41586-026-11139-6

Keywords: glycogen, RNF213, ubiquitylation, autophagy, polyglucosan, E3 ligase, cryo-EM, CBM20, astrocytes, neurodegeneration, LUBAC, SQSTM1

The research, led by Junrui Luo and Zhiqiang Liu at Henan Polytechnic University in Jiaozuo, China, focused on TRIM37, a member of the tripartite motif family of E3 ubiquitin ligases. These enzymes act as molecular quality-control agents, attaching small ubiquitin protein tags to specific target molecules, which then marks those targets for destruction or alters their behavior. TRIM37 had already been implicated in cancer development and in maintaining the health of centrioles, the barrel-shaped structures from which cilia are built. But its precise role in the assembly of primary cilia, a process biologists call ciliogenesis, had remained murky until now.

To probe that role, the team worked with two widely used laboratory cell lines: human retinal pigment epithelial cells, known as RPE1 cells, which are a standard model for studying cilia, and HK2 cells, a human kidney cell line. Both of these cell types normally grow prominent primary cilia when they exit the active cell cycle and settle into a quiescent state. When the researchers used RNA interference to knock down TRIM37 expression, they observed a striking effect: the fraction of cells that managed to grow cilia dropped significantly, and the cilia that did form were noticeably shorter than normal. Importantly, the team verified that this defect was not simply a side effect of altered cell cycle progression, ruling out one obvious alternative explanation.

A key clue to the mechanism came from the location of the protein itself. Using fluorescence microscopy, the researchers found that TRIM37 accumulates at the basal body, the modified centriole that anchors the cilium to the cell and serves as the gateway through which building blocks are ferried into the growing organelle. This strategic positioning suggested that TRIM37 might be doing more than just housekeeping at the cilium’s foundation. It hinted that the protein could be actively managing the local environment needed for ciliary assembly, possibly by coordinating the delivery or removal of materials at the base of the structure.

That suspicion led the investigators to autophagy, the cell’s internal recycling program. During autophagy, the cell engulfs damaged proteins and organelles in double-membraned vesicles called autophagosomes, which then fuse with lysosomes, the acidic compartments where the cargo is broken down and its components are returned for reuse. Autophagy has a complicated, two-sided relationship with cilia: at moderate levels it can help clear inhibitors of ciliary assembly, but excessive or insufficient autophagic activity can disrupt cilium formation. The researchers discovered that when TRIM37 was depleted, cells accumulated LC3-II, a lipidated form of a protein that decorates autophagosomal membranes, along with p62, also known as SQSTM1, a cargo receptor that shuttles tagged material into autophagosomes. At the same time, levels of Beclin1 and WIPI2, two proteins essential for launching the autophagy program, declined, indicating that the initiation of autophagy itself was being suppressed.

To determine whether the accumulated autophagic machinery was actually working, the team deployed bafilomycin A1, a toxin that blocks the final step of autophagy by preventing the acidification of lysosomes and the fusion of autophagosomes with them. By comparing autophagic flux, the complete throughput of the recycling pipeline, in the presence and absence of this blocker, the researchers confirmed that TRIM37-deficient cells suffered from genuine flux impairment. An independent immunofluorescence assay measuring the colocalization of LC3 with LAMP2, a lysosomal membrane protein, painted the same picture: autophagosome formation was reduced, and the fusion of autophagosomes with lysosomes was defective. In other words, losing TRIM37 did not merely slow the recycling line at one checkpoint; it jammed the entire conveyor belt.

The next question was whether TRIM37’s enzymatic activity, its ability to transfer ubiquitin tags, was required for these effects. The researchers performed functional complementation experiments, re-introducing TRIM37 variants into depleted cells and testing whether the protein could rescue normal cilium growth and autophagic balance. The results were unambiguous: only a version of TRIM37 with intact E3 ubiquitin ligase activity could restore normal ciliogenesis and autophagic homeostasis. A catalytically dead variant could not. This finding elevated TRIM37 from a passive structural component to an active enzymatic regulator whose chemical function is the linchpin of the whole process.

Having established that TRIM37’s ligase activity was essential, the team searched for the critical substrate and found it in p62, the very cargo receptor that had piled up in TRIM37-depleted cells. The experiments showed that TRIM37 directly mediates the ubiquitination of SQSTM1/p62, promoting its turnover and thereby keeping autophagic activity within the proper range. When TRIM37 is absent, p62 accumulates unchecked, and the resulting imbalance disrupts both the initiation of autophagy and the maturation of autophagosomes, which in turn sabotages the carefully choreographed process of cilium construction.

The most convincing demonstration of this regulatory axis came from a double-knockdown experiment. When the researchers simultaneously depleted both TRIM37 and SQSTM1/p62, the ciliogenesis defects and autophagic abnormalities caused by losing TRIM37 alone were substantially alleviated. This genetic epistasis experiment, a classic strategy for ordering genes into a pathway, showed that p62 acts downstream of TRIM37 and that removing the problematic accumulation of p62 can compensate for the loss of its regulator. Together, the findings define a novel TRIM37–SQSTM1/p62–autophagy signaling axis that modulates mammalian ciliogenesis, adding a new branch to the molecular regulatory network that biologists have been mapping for decades.

The implications of this work extend beyond basic cell biology. TRIM37 is already known as the gene mutated in mulibrey nanism, a rare inherited growth disorder, and its involvement in centriole maintenance and tumorigenesis has made it a subject of intense interest. By connecting this ubiquitin ligase to the autophagy machinery and to ciliary assembly, the study offers a mechanistic framework that could eventually inform research into ciliopathies, kidney disease, and cancers in which autophagy and ciliary signaling go awry. It also underscores a growing theme in modern cell biology: organelle construction is not an isolated program but an integrated process that depends on the cell’s recycling systems running at exactly the right tempo. As researchers continue to untangle the connections between ubiquitination, autophagy, and cilia, the TRIM37–p62 axis identified here provides a clear example of how a single enzymatic regulator can coordinate two fundamental cellular systems to build one of the cell’s most important sensory structures.

Subject of Research: Regulation of primary ciliogenesis by the E3 ubiquitin ligase TRIM37 through p62 ubiquitination and autophagy control

Article Title: Ciliogenesis is regulated by TRIM37 through ubiquitinating p62 and controlling the autophagy pathway

Article References: Luo, J., Zhang, X., Zhao, C., Zhang, Y., Chen, W., Wang, Z., Li, S., & Liu, Z. (2026). Ciliogenesis is regulated by TRIM37 through ubiquitinating p62 and controlling the autophagy pathway. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06454-0

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06454-0

Keywords: TRIM37, ciliogenesis, primary cilia, autophagy, p62, SQSTM1, ubiquitination, E3 ubiquitin ligase, basal body, autophagic flux, ciliopathies, cell biology

Ubiquitin is a small protein tag that cells attach to other proteins to change their fate, and the way ubiquitin molecules are linked together matters enormously. Whereas K48-linked chains typically condemn proteins to destruction by the proteasome, K63-linked chains serve a very different purpose: they orchestrate protein interactions, intracellular trafficking, and signaling activity without triggering degradation. UBE2N, also known as Ubc13, is the specialized E2 enzyme that builds these K63-linked chains, and its role in MASH had remained almost entirely unexplored until now.

The researchers began by examining liver tissue from both human patients and mouse models of MASH, and they found a consistent pattern: UBE2N was markedly downregulated in hepatocytes under metabolic stress. Digging into the mechanism, they identified THAP11 as a transcriptional repressor that binds the UBE2N promoter during disease progression, effectively silencing the enzyme as fatty acids accumulate. Single-nucleus RNA sequencing and digital spatial transcriptomics confirmed that this drop in UBE2N expression is specifically concentrated in hepatocytes rather than other liver cell types.

To establish causality, the team generated mice lacking Ube2n selectively in hepatocytes. When these animals were placed on a western diet, they developed dramatically worse MASH and liver fibrosis than their normal counterparts. Serum liver enzymes rose, inflammatory and fibrogenic genes were upregulated, and the livers showed extensive fat accumulation and scarring. Crucially, when the researchers overexpressed UBE2N in the liver, the pathological phenotypes reversed and hepatic homeostasis was largely restored, demonstrating that the enzyme is not merely a bystander but an active protector.

The mechanism underlying this protection turned out to involve two intimately connected processes: mitophagy and PANoptosis. Mitophagy is the cellular quality-control system that identifies damaged mitochondria and delivers them to lysosomes for degradation, preventing the release of inflammatory mitochondrial contents. PANoptosis, by contrast, is a recently defined form of inflammatory programmed cell death that combines features of pyroptosis, apoptosis, and necroptosis simultaneously, unleashing a potent inflammatory storm. The new study shows that when UBE2N is lost, mitophagy collapses and PANoptosis erupts, creating the destructive combination that drives MASH forward.

At the molecular level, the researchers traced how UBE2N keeps mitophagy running smoothly. Working with the PARKIN pathway, they found that UBE2N catalyzes K63-linked ubiquitination of p62, also known as SQSTM1, at a specific site, lysine 420. This modification acts as a trafficking signal, promoting the translocation of K63-tagged p62 into damaged mitochondria where it serves as an autophagy receptor, tethering the cargo to the autophagic machinery for clearance. In cells lacking UBE2N, this modification fails to occur, p62 fails to reach the mitochondria, and damaged organelles accumulate unchecked.

But the story has an unexpected twist. When p62 cannot reach mitochondria, it accumulates in the cytoplasm, and this cytoplasmic buildup has consequences of its own. The researchers found that cytoplasmic p62 aggregation drives hyperactivation of NRF2, a transcription factor normally considered protective against oxidative stress. While NRF2 activation is beneficial in moderation, the study demonstrates that excessive, sustained NRF2 signaling in this context actively promotes PANoptosis and worsens liver damage. This finding challenges the simplistic view of NRF2 as an unambiguously protective factor in liver disease.

To prove that p62 accumulation is truly the culprit, the team generated mice lacking both Ube2n and Sqstm1 in hepatocytes. Remarkably, this additional deletion substantially mitigated the severe liver pathology caused by Ube2n loss alone, confirming that the damaging effects of UBE2N deficiency flow largely through cytoplasmic p62 buildup. The result establishes p62 as a proof-of-concept therapeutic target: if its cytoplasmic accumulation can be prevented or its mitochondrial routing restored, the downstream cascade of NRF2 hyperactivation and PANoptosis might be interrupted.

The implications extend beyond basic biology. MASH currently affects hundreds of millions of people worldwide, and only recently did the first targeted therapy, the thyroid hormone receptor-beta agonist resmetirom, gain approval. The identification of UBE2N and the p62 trafficking pathway offers an entirely new axis for intervention, one that operates at the level of mitochondrial quality control rather than lipid metabolism alone. Hepatic targeting of Ube2n in the mouse models prevented western diet-induced MASH progression, suggesting that gene-based or small-molecule approaches aimed at restoring this pathway could be feasible.

There remain significant challenges before this biology can be translated into treatments. UBE2N participates in immune receptor signaling and skin homeostasis, so systemic manipulation carries risks of off-target effects, and the precise dose, timing, and delivery method for hepatic intervention would need careful optimization. Nonetheless, the study provides an unusually complete mechanistic arc, from a transcriptional repressor silencing a ubiquitin enzyme, through defective mitochondrial tagging and cytoplasmic protein aggregation, to inflammatory cell death and fibrosis, and it does so with consistent evidence from human tissue, mouse genetics, and cell biology. For a field desperate for new molecular handles on a growing epidemic, UBE2N and its p62-dependent pathway represent one of the most compelling new entries in years.

Subject of Research: Role of UBE2N-regulated p62 mitophagy and PANoptosis in metabolic dysfunction-associated steatohepatitis

Article Title: UBE2N deficiency contributes to MASH development via p62-regulated mitophagy and PANoptosis

Article References: UBE2N deficiency contributes to MASH development via p62-regulated mitophagy and PANoptosis. (n.d.). https://doi.org/10.1038/s42255-026-01590-0

Image Credits: AI Generated

DOI: 10.1038/s42255-026-01590-0

Keywords: UBE2N, MASH, p62, SQSTM1, mitophagy, PANoptosis, K63-linked ubiquitination, PARKIN, NRF2, THAP11, liver fibrosis, Nature Metabolism