The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3.
The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3.
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DOI：
10.1038/s41467-022-35501-0
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发表时间：
2022-12-21
影响因子：
16.6
通讯作者：
Komatsu, Masaaki
中科院分区：
文献类型：
--
作者：
Ishimura, Ryosuke;El-Gowily, Afnan H.;Noshiro, Daisuke;Komatsu-Hirota, Satoko;Ono, Yasuko;Shindo, Mayumi;Hatta, Tomohisa;Abe, Manabu;Uemura, Takefumi;Lee-Okada, Hyeon-Cheol;Mohamed, Tarek M.;Yokomizo, Takehiko;Ueno, Takashi;Sakimura, Kenji;Natsume, Tohru;Sorimachi, Hiroyuki;Inada, Toshifumi;Waguri, Satoshi;Noda, Nobuo N.;Komatsu, Masaaki
泛素样蛋白（UBLs）的蛋白质修饰放大了有限的基因组信息，并调节了多种细胞过程，包括翻译，自噬和抗病毒途径。泛素折叠修饰因子1（UFM 1）是一种通过泛素化（一种类似于泛素化的反应）与细胞内蛋白共价结合的UBL。Ufmylation参与诸如内质网（ER）相关蛋白质降解、ER处的核糖体相关蛋白质质量控制和ER吞噬的过程。然而，目前还不清楚如何ufmylation调节这种独特的ER相关功能。在这里，我们确定UFM 1底物，NADH-细胞色素b5还原酶3（CYB 5 R3），定位于ER膜上。CYB 5 R3的磺酰化依赖于ER上的E3组分UFL 1和UFBP 1，并将CYB 5 R3转化为其非活性形式。UFBP 1通过UFM 1相互作用基序识别Ufmylated CYB 5 R3，UFM 1相互作用基序在CYB 5 R3的进一步Ufmylated中起重要作用。Ufmylated CYB 5 R3在溶酶体中降解，这取决于自噬相关蛋白Atg 7-和自噬接头蛋白CDK 5 RAP 3。CYB 5 R3和UFM 1系统相关基因的突变导致遗传性发育障碍，而UFMylation缺陷型Cyb 5 r3基因敲入小鼠表现出小头畸形。我们的研究结果表明，CYB 5 R3的ufmylation诱导ER-吞噬，这是必不可少的大脑发育。UFM 1系统是一种泛素样结合系统，对内质网（ER）的稳态至关重要。在这里，作者发现CYB 5 R3与UFM 1共价结合，UFM 1成为ER-吞噬的信号，ER的选择性自噬。
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. The UFM1 system, a ubiquitin-like conjugation system is crucial for endoplasmic reticulum (ER) homeostasis. Here, authors found that CYB5R3 is covalently conjugated with UFM1, which becomes a signal for ER-phagy, a selective autophagy of ER.
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