Peroxisome quality control is gated by a dynamic ATF6α-ABCD3 tether
- 1Altos Labs; Buck Institute for Research on Aging (current)
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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BibTeX
@misc{noddings2026peroxisome,
title = {{Peroxisome quality control is gated by a dynamic ATF6α-ABCD3 tether}},
author = {C. M. Noddings and R. Mukherjee and C. Peukert and T. G. Laughlin and J. Wang and B. T. Walters and T.-W. Lu and T. Croll and D. Eismann and S. Harel and A. Xu and K. Kim and M. Gupta and J. Crawford and C. P. Arthur and D. Itzhak and M. Costa-Mattioli and J. Rudolph and A. Ashkenazi and P. Walter},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.05.756567},
url = {https://www.biorxiv.org/content/10.64898/2026.10.05.756567v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Peroxisome quality control is gated by a dynamic ATF6α-ABCD3 tether
AU - C. M. Noddings
AU - R. Mukherjee
AU - C. Peukert
AU - T. G. Laughlin
AU - J. Wang
AU - B. T. Walters
AU - T.-W. Lu
AU - T. Croll
AU - D. Eismann
AU - S. Harel
AU - A. Xu
AU - K. Kim
AU - M. Gupta
AU - J. Crawford
AU - C. P. Arthur
AU - D. Itzhak
AU - M. Costa-Mattioli
AU - J. Rudolph
AU - A. Ashkenazi
AU - P. Walter
PY - 2026
DA - 2026/10/05
PB - bioRxiv
DO - 10.64898/2026.10.05.756567
UR - https://www.biorxiv.org/content/10.64898/2026.10.05.756567v1
AB - 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.
ER -