2. Academic Validation
  3. Ubiquitination regulates ER-phagy and remodelling of endoplasmic reticulum

Ubiquitination regulates ER-phagy and remodelling of endoplasmic reticulum

  • Nature. 2023 May 24. doi: 10.1038/s41586-023-06089-2.
Alexis González # 1,  Adriana Covarrubias-Pinto # 1,  Ramachandra M Bhaskara 1 2 3,  Marius Glogger 4,  Santosh K Kuncha 1 2,  Audrey Xavier 1 2,  Eric Seemann 5,  Mohit Misra 1 2,  Marina E Hoffmann 1,  Bastian Bräuning 6,  Ashwin Balakrishnan 4,  Britta Qualmann 5,  Volker Dötsch 7,  Brenda A Schulman 6,  Michael M Kessels 5,  Christian A Hübner 8,  Mike Heilemann 4,  Gerhard Hummer 3 9,  Ivan Dikić 10 11 12
Affiliations

Affiliations

  • 1 Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany.
  • 2 Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt am Main, Germany.
  • 3 Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt am Main, Germany.
  • 4 Institute of Physical and Theoretical Chemistry, Goethe University Frankfurt, Frankfurt, Germany.
  • 5 Institute of Biochemistry I, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany.
  • 6 Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany.
  • 7 Institute of Biophysical Chemistry, Center for Biomolecular Magnetic Resonance, Goethe University Frankfurt, Frankfurt, Germany.
  • 8 Institute of Human Genetics, University Hospital Jena, Friedrich Schiller University, Jena, Germany.
  • 9 Institute of Biophysics, Goethe University Frankfurt, Frankfurt am Main, Germany.
  • 10 Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany. dikic@biochem2.uni-frankfurt.de.
  • 11 Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt am Main, Germany. dikic@biochem2.uni-frankfurt.de.
  • 12 Fraunhofer Institute of Translational Medicine and Pharmacology, Frankfurt am Main, Germany. dikic@biochem2.uni-frankfurt.de.
  • # Contributed equally.
PMID: 37225996 DOI: 10.1038/s41586-023-06089-2
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.

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