Peroxisome quality control is gated by a dynamic ATF6α-ABCD3 tether

Noddings, C. M.; Mukherjee, R.; Peukert, C.; Laughlin, T. G.; Wang, J.; Walters, B. T.; Lu, T.-W.; Croll, T.; Eismann, D.; Harel, S.; Xu, A.; Kim, K.; Gupta, M.; Crawford, J.; Arthur, C. P.; Itzhak, D.; Costa-Mattioli, M.; Rudolph, J.; Ashkenazi, A.; Walter, P.

doi:10.64898/2026.10.05.756567

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bioRxiv · 10.64898/2026.10.05.756567

Peroxisome quality control is gated by a dynamic ATF6α-ABCD3 tether

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Abstract

The endoplasmic reticulum (ER) coordinates protein folding and lipid biosynthesis, while peroxisomes govern fatty-acid catabolism and redox balance. However, little is known about the mechanisms by which these organelles communicate. Here we show that activating transcription factor 6 (ATF6), a cytoprotective ER-resident sensor of the unfolded protein response (UPR), forms a molecular tether that zippers the ER and peroxisomes together at a 23-nm intermembrane distance. ATF6 achieves this by inserting a short segment of its unstructured N-terminal cytosolic tail into the solvated transmembrane cavity of the peroxisomal ABC-type lipid transporter ABCD3, trapping it in an off-state. This interaction is reinforced by Ceapin, a previously identified small molecule molecular-glue ligand, which promotes ER-peroxisome contact formation. The junctions serve as a scaffold that can initiate peroxisome turnover by p62-triggered autophagy (pexophagy), as enhanced lipid processing resulting from organelle zippering leads to peroxisome damage due to excessive reactive oxygen species (ROS) accumulation. These findings define ATF6 as a non-transcriptional regulator of organelle quality control and provide a template for engineering Ceapin analogues against ATF6/ABCD3-dependent colorectal and hepatocellular cancers and related diseases.

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Noddings, C. M., Mukherjee, R., Peukert, C., Laughlin, T. G., Wang, J., Walters, B. T., Lu, T.-W., Croll, T., Eismann, D., Harel, S., Xu, A., Kim, K., Gupta, M., Crawford, J., Arthur, C. P., Itzhak, D., Costa-Mattioli, M., Rudolph, J., Ashkenazi, A., Walter, P.. 2026-10-06. Peroxisome quality control is gated by a dynamic ATF6α-ABCD3 tether. https://doi.org/10.64898/2026.10.05.756567

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