Author
Listed:
- Alexis González
(Goethe University Frankfurt)
- Adriana Covarrubias-Pinto
(Goethe University Frankfurt)
- Ramachandra M. Bhaskara
(Goethe University Frankfurt
Goethe University Frankfurt
Max Planck Institute of Biophysics)
- Marius Glogger
(Goethe University Frankfurt)
- Santosh K. Kuncha
(Goethe University Frankfurt
Goethe University Frankfurt)
- Audrey Xavier
(Goethe University Frankfurt
Goethe University Frankfurt)
- Eric Seemann
(Friedrich Schiller University Jena)
- Mohit Misra
(Goethe University Frankfurt
Goethe University Frankfurt)
- Marina E. Hoffmann
(Goethe University Frankfurt)
- Bastian Bräuning
(Max Planck Institute of Biochemistry)
- Ashwin Balakrishnan
(Goethe University Frankfurt)
- Britta Qualmann
(Friedrich Schiller University Jena)
- Volker Dötsch
(Goethe University Frankfurt)
- Brenda A. Schulman
(Max Planck Institute of Biochemistry)
- Michael M. Kessels
(Friedrich Schiller University Jena)
- Christian A. Hübner
(University Hospital Jena, Friedrich Schiller University)
- Mike Heilemann
(Goethe University Frankfurt)
- Gerhard Hummer
(Max Planck Institute of Biophysics
Goethe University Frankfurt)
- Ivan Dikić
(Goethe University Frankfurt
Goethe University Frankfurt
Fraunhofer Institute of Translational Medicine and Pharmacology)
Abstract
The endoplasmic reticulum (ER) undergoes continuous remodelling via a selective autophagy pathway, known as ER-phagy1. ER-phagy receptors have a central role in this process2, but the regulatory mechanism remains largely unknown. Here we report that ubiquitination of the ER-phagy receptor FAM134B within its reticulon homology domain (RHD) promotes receptor clustering and binding to lipidated LC3B, thereby stimulating ER-phagy. Molecular dynamics (MD) simulations showed how ubiquitination perturbs the RHD structure in model bilayers and enhances membrane curvature induction. Ubiquitin molecules on RHDs mediate interactions between neighbouring RHDs to form dense receptor clusters that facilitate the large-scale remodelling of lipid bilayers. Membrane remodelling was reconstituted in vitro with liposomes and ubiquitinated FAM134B. Using super-resolution microscopy, we discovered FAM134B nanoclusters and microclusters in cells. Quantitative image analysis revealed a ubiquitin-mediated increase in FAM134B oligomerization and cluster size. We found that the E3 ligase AMFR, within multimeric ER-phagy receptor clusters, catalyses FAM134B ubiquitination and regulates the dynamic flux of ER-phagy. Our results show that ubiquitination enhances RHD functions via receptor clustering, facilitates ER-phagy and controls ER remodelling in response to cellular demands.
Suggested Citation
Alexis González & Adriana Covarrubias-Pinto & Ramachandra M. Bhaskara & Marius Glogger & Santosh K. Kuncha & Audrey Xavier & Eric Seemann & Mohit Misra & Marina E. Hoffmann & Bastian Bräuning & Ashwin, 2023.
"Ubiquitination regulates ER-phagy and remodelling of endoplasmic reticulum,"
Nature, Nature, vol. 618(7964), pages 394-401, June.
Handle:
RePEc:nat:nature:v:618:y:2023:i:7964:d:10.1038_s41586-023-06089-2
DOI: 10.1038/s41586-023-06089-2
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