| 著者 |
Mao G, Ito S, Ishimura R, Sakamaki JI, Sasaki R, Uemura T, Ishikawa KI, Komatsu-Hirota S, Akamatsu W, Abe M, Waguri S, Bijarnia-Mahay S, Noda NN, Inada T, Komatsu M.
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| Abstract |
The ubiquitin-fold modifier 1 (UFM1) pathway is essential for endoplasmic-reticulum-associated ribosome quality control (ER-RQC) through UFMylation of the 60S ribosomal protein RPL26, but the regulation and physiological significance of UFM1 deconjugation remain poorly understood. Here, we identify the ER-anchored UFSP2-ODR4 complex as a spatially confined deUFMylation module critical for neuronal proteostasis. Structural modeling and biochemical analyses show that ODR4 recruits UFSP2 to the ER, enabling efficient deUFMylation of RPL26. Disruption of the UFSP2-ODR4 interaction causes the accumulation of UFMylated RPL26 and defective ER-RQC. Neural progenitor-specific knockin mice expressing a catalytically inactive UFSP2 mutant exhibit perinatal lethality, microcephaly, and neuronal apoptosis. We also identify a patient with biallelic UFC1 mutations that enhance UFL1 binding and induce hyper-UFMylation of RPL26 in patient-derived neurons. These findings establish spatially confined deUFMylation as a critical mechanism for safeguarding neuronal proteostasis.
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