Ubiquitination regulates ER-phagy and remodelling of endoplasmic reticulum

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 Balakrishnan, Britta Qualmann, Volker Dötsch, Brenda A. Schulman, Michael M. Kessels, Christian A. Hübner, Mike Heilemann, Gerhard Hummer and Ivan Dikić ()
Additional contact information
Alexis González: Goethe University Frankfurt
Adriana Covarrubias-Pinto: Goethe University Frankfurt
Ramachandra M. Bhaskara: Goethe University Frankfurt
Marius Glogger: Goethe University Frankfurt
Santosh K. Kuncha: Goethe University Frankfurt
Audrey Xavier: Goethe University Frankfurt
Eric Seemann: Friedrich Schiller University Jena
Mohit Misra: 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
Ivan Dikić: Goethe University Frankfurt

Nature, 2023, vol. 618, issue 7964, 394-401

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06089-2

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