Kavli Affiliate: Peter Walter
| Authors: Chari M Noddings, Rukmini Mukherjee, Carsten Peukert, Thomas G Laughlin, Jing Wang, Benjamin T Walters, Tsan-Wen Lu, Tristan Croll, Deniz Eismann, Shelly Harel, Angela Xu, Kibeom Kim, Meghna Gupta, James Crawford, Christopher P Arthur, Daniel Itzhak, Mauro Costa-Mattioli, Joachim Rudolph, Avi Ashkenazi and Peter Walter
| Summary:
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 (ATF6α), a cytoprotective ER-resident sensor of the unfolded protein response (UPR)1–4, forms a molecular tether that zippers the ER and peroxisomes together at a 23-nm intermembrane distance. ATF6α 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 formation5–7. 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 ATF6α as a non-transcriptional regulator of organelle quality control and provide a template for engineering Ceapin analogues against ATF6α/ABCD3-dependent colorectal and hepatocellular cancers and related diseases.