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