E3 Ligase TRIM37 Steers Cilia Growth by Tagging p62 and Tuning Autophagy

Deep inside nearly every cell in the human body, a tiny antenna-like structure called the primary cilium extends from the cell surface, gathering chemical and mechanical signals that tell the cell how to grow, divide, and respond to its environment. When these structures fail to form properly, the consequences can be devastating, giving rise to a family of inherited disorders known as ciliopathies, which can affect the kidneys, eyes, brain, and skeleton. A new study published in the journal Cellular and Molecular Life Sciences has now uncovered a previously hidden control mechanism governing how cells build these essential organelles, and it centers on an unexpected partnership between a ubiquitin ligase called TRIM37 and the cellular recycling system known as autophagy.

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