The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
21 12 2022
21 12 2022
Historique:
received:
28
01
2022
accepted:
07
12
2022
entrez:
21
12
2022
pubmed:
22
12
2022
medline:
24
12
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36543799
doi: 10.1038/s41467-022-35501-0
pii: 10.1038/s41467-022-35501-0
pmc: PMC9772183
doi:
Substances chimiques
Cdk5rap3 protein, mouse
0
Cell Cycle Proteins
0
Cytochrome-B(5) Reductase
EC 1.6.2.2
Ubiquitins
0
Ufm1 protein, mouse
0
Cyb5r3 protein, mouse
EC 1.6.2.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7857Informations de copyright
© 2022. The Author(s).
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