Heteromeric clusters of ubiquitinated ER-shaping proteins drive ER-phagy

Hector Foronda, Yangxue Fu, Adriana Covarrubias-Pinto, Hartmut T. Bocker, Alexis González, Eric Seemann, Patricia Franzka, Andrea Bock, Ramachandra M. Bhaskara, Lutz Liebmann, Marina E. Hoffmann, Istvan Katona, Nicole Koch, Joachim Weis, Ingo Kurth, Joseph G. Gleeson, Fulvio Reggiori, Gerhard Hummer, Michael M. Kessels, Britta Qualmann, Muriel Mari, Ivan Dikić () and Christian A. Hübner ()
Additional contact information
Hector Foronda: Jena University Hospital, Friedrich Schiller University
Yangxue Fu: Goethe University School of Medicine
Adriana Covarrubias-Pinto: Goethe University School of Medicine
Hartmut T. Bocker: Jena University Hospital, Friedrich Schiller University
Alexis González: Goethe University School of Medicine
Eric Seemann: Jena University Hospital, Friedrich Schiller University
Patricia Franzka: Jena University Hospital, Friedrich Schiller University
Andrea Bock: Jena University Hospital, Friedrich Schiller University
Ramachandra M. Bhaskara: Goethe University School of Medicine
Lutz Liebmann: Jena University Hospital, Friedrich Schiller University
Marina E. Hoffmann: Goethe University School of Medicine
Istvan Katona: RWTH Aachen University Hospital
Nicole Koch: Jena University Hospital, Friedrich Schiller University
Joachim Weis: RWTH Aachen University Hospital
Ingo Kurth: Jena University Hospital, Friedrich Schiller University
Joseph G. Gleeson: University of California, San Diego
Fulvio Reggiori: University of Groningen, University Medical Center Groningen
Gerhard Hummer: Max Planck Institute of Biophysics
Michael M. Kessels: Jena University Hospital, Friedrich Schiller University
Britta Qualmann: Jena University Hospital, Friedrich Schiller University
Muriel Mari: University of Groningen, University Medical Center Groningen
Ivan Dikić: Goethe University School of Medicine
Christian A. Hübner: Jena University Hospital, Friedrich Schiller University

Nature, 2023, vol. 618, issue 7964, 402-410

Abstract: Abstract Membrane-shaping proteins characterized by reticulon homology domains play an important part in the dynamic remodelling of the endoplasmic reticulum (ER). An example of such a protein is FAM134B, which can bind LC3 proteins and mediate the degradation of ER sheets through selective autophagy (ER-phagy)1. Mutations in FAM134B result in a neurodegenerative disorder in humans that mainly affects sensory and autonomic neurons2. Here we report that ARL6IP1, another ER-shaping protein that contains a reticulon homology domain and is associated with sensory loss3, interacts with FAM134B and participates in the formation of heteromeric multi-protein clusters required for ER-phagy. Moreover, ubiquitination of ARL6IP1 promotes this process. Accordingly, disruption of Arl6ip1 in mice causes an expansion of ER sheets in sensory neurons that degenerate over time. Primary cells obtained from Arl6ip1-deficient mice or from patients display incomplete budding of ER membranes and severe impairment of ER-phagy flux. Therefore, we propose that the clustering of ubiquitinated ER-shaping proteins facilitates the dynamic remodelling of the ER during ER-phagy and is important for neuronal maintenance.

Date: 2023
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DOI: 10.1038/s41586-023-06090-9

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