The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3

Ryosuke Ishimura, Afnan H. El-Gowily, Daisuke Noshiro, Satoko Komatsu-Hirota, Yasuko Ono, Mayumi Shindo, Tomohisa Hatta, Manabu Abe, Takefumi Uemura, Hyeon-Cheol Lee-Okada, Tarek M. Mohamed, Takehiko Yokomizo, Takashi Ueno, Kenji Sakimura, Tohru Natsume, Hiroyuki Sorimachi, Toshifumi Inada, Satoshi Waguri, Nobuo N. Noda and Masaaki Komatsu ()
Additional contact information
Ryosuke Ishimura: Juntendo University Graduate School of Medicine, Bunkyo-ku
Afnan H. El-Gowily: Juntendo University Graduate School of Medicine, Bunkyo-ku
Daisuke Noshiro: Hokkaido University
Satoko Komatsu-Hirota: Juntendo University Graduate School of Medicine, Bunkyo-ku
Yasuko Ono: Tokyo Metropolitan Institute of Medical Science, Setagaya-ku
Mayumi Shindo: Tokyo Metropolitan Institute of Medical Science, Setagaya-ku
Tomohisa Hatta: Biological Information Research Center (JBIRC), Kohtoh-ku
Manabu Abe: Niigata University, Chuo-ku
Takefumi Uemura: Fukushima Medical University School of Medicine, Hikarigaoka
Hyeon-Cheol Lee-Okada: Juntendo University Graduate School of Medicine, Bunkyo-ku
Tarek M. Mohamed: Tanta University
Takehiko Yokomizo: Juntendo University Graduate School of Medicine, Bunkyo-ku
Takashi Ueno: Juntendo University Graduate School of Medicine, Bunkyo-ku
Kenji Sakimura: Niigata University, Chuo-ku
Tohru Natsume: Biological Information Research Center (JBIRC), Kohtoh-ku
Hiroyuki Sorimachi: Tokyo Metropolitan Institute of Medical Science, Setagaya-ku
Toshifumi Inada: The University of Tokyo
Satoshi Waguri: Fukushima Medical University School of Medicine, Hikarigaoka
Nobuo N. Noda: Hokkaido University
Masaaki Komatsu: Juntendo University Graduate School of Medicine, Bunkyo-ku

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Protein modification by ubiquitin-like proteins (UBLs) amplifies limited genome information and regulates diverse cellular processes, including translation, autophagy and antiviral pathways. Ubiquitin-fold modifier 1 (UFM1) is a UBL covalently conjugated with intracellular proteins through ufmylation, a reaction analogous to ubiquitylation. Ufmylation is involved in processes such as endoplasmic reticulum (ER)-associated protein degradation, ribosome-associated protein quality control at the ER and ER-phagy. However, it remains unclear how ufmylation regulates such distinct ER-related functions. Here we identify a UFM1 substrate, NADH-cytochrome b5 reductase 3 (CYB5R3), that localizes on the ER membrane. Ufmylation of CYB5R3 depends on the E3 components UFL1 and UFBP1 on the ER, and converts CYB5R3 into its inactive form. Ufmylated CYB5R3 is recognized by UFBP1 through the UFM1-interacting motif, which plays an important role in the further uyfmylation of CYB5R3. Ufmylated CYB5R3 is degraded in lysosomes, which depends on the autophagy-related protein Atg7- and the autophagy-adaptor protein CDK5RAP3. Mutations of CYB5R3 and genes involved in the UFM1 system cause hereditary developmental disorders, and ufmylation-defective Cyb5r3 knock-in mice exhibit microcephaly. Our results indicate that CYB5R3 ufmylation induces ER-phagy, which is indispensable for brain development.

Date: 2022
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DOI: 10.1038/s41467-022-35501-0

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