TY - JOUR
T1 - Heteromeric clusters of ubiquitinated ER-shaping proteins drive ER-phagy
AU - Foronda, Hector
AU - Fu, Yangxue
AU - Covarrubias-Pinto, Adriana
AU - Bocker, Hartmut T.
AU - González, Alexis
AU - Seemann, Eric
AU - Franzka, Patricia
AU - Bock, Andrea
AU - Bhaskara, Ramachandra M.
AU - Liebmann, Lutz
AU - Hoffmann, Marina E.
AU - Katona, Istvan
AU - Koch, Nicole
AU - Weis, Joachim
AU - Kurth, Ingo
AU - Gleeson, Joseph G.
AU - Reggiori, Fulvio
AU - Hummer, Gerhard
AU - Kessels, Michael M.
AU - Qualmann, Britta
AU - Mari, Muriel
AU - Dikić, Ivan
AU - Hübner, Christian A.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/6/8
Y1 - 2023/6/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85160241557&partnerID=8YFLogxK
U2 - 10.1038/s41586-023-06090-9
DO - 10.1038/s41586-023-06090-9
M3 - Article
C2 - 37225994
AN - SCOPUS:85160241557
SN - 0028-0836
VL - 618
SP - 402
EP - 410
JO - Nature
JF - Nature
ER -