A cross-kingdom conserved ER-phagy receptor maintains endoplasmic reticulum homeostasis during stress

Stephani, Madlen and Picchianti, Lorenzo and Gajic, Alexander and Beveridge, Rebecca and Skarwan, Emilio and Sanchez de Medina Hernandez, Victor and Mohseni, Azadeh and Clavel, Marion and Zeng, Yonglung and Naumann, Christin and Matuszkiewicz, Mateusz and Turco, Eleonora and Loefke, Christian and Li, Baiying and Durnberger, Gerhard and Schutzbier, Michael and Chen, Hsiao Tieh and Abdrakhmanov, Alibek and Savova, Adriana and Chia, Khong-Sam and Djamei, Armin and Schaffner, Irene and Abel, Steffen and Jiang, Liwen and Mechtler, Karl and Ikeda, Fumiyo and Martens, Sascha and Clausen, Tim and Dagdas, Yasin (2020) A cross-kingdom conserved ER-phagy receptor maintains endoplasmic reticulum homeostasis during stress. Preprint / Working Paper. bioRxiv, Cold Spring Harbor, NY.. (https://doi.org/10.1101/2020.03.18.995316)

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Eukaryotes have evolved various quality control mechanisms to promote proteostasis in the ER. Selective removal of certain ER domains via autophagy (termed as ER-phagy) has emerged as a major quality control mechanism. However, the degree to which ER-phagy is employed by other branches of ER-quality control remains largely elusive. Here, we identify a cytosolic protein, C53, that is specifically recruited to autophagosomes during ER-stress, in both plant and mammalian cells. C53 interacts with ATG8 via a distinct binding epitope, featuring a shuffled ATG8 interacting motif (sAIM). C53 senses proteotoxic stress in the ER lumen by forming a tripartite receptor complex with the ER-associated ufmylation ligase UFL1 and its membrane adaptor DDRGK1. The C53/UFL1/DDRGK1 receptor complex is activated by stalled ribosomes and induces the degradation of internal or passenger proteins in the ER. Consistently, the C53 receptor complex and ufmylation mutants are highly susceptible to ER stress. Thus, C53 forms an ancient quality control pathway that bridges selective autophagy with ribosome-associated quality control at the ER.