Loss of peptide: N -glycanase causes proteasome dysfunction mediated by a sugar-recognizing ubiquitin ligase
Loss of peptide: N -glycanase causes proteasome dysfunction mediated by a sugar-recognizing ubiquitin ligase
复制标题
肽丢失：N-聚糖酶导致由糖识别泛素连接酶介导的蛋白酶体功能障碍
DOI：
10.1073/pnas.2102902118
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Suzuki Tadashi
中科院分区：
文献类型：
--
作者：
Yoshida Yukiko;Asahina Makoto;Murakami Arisa;Kawawaki Junko;Yoshida Meari;Fujinawa Reiko;Iwai Kazuhiro;Tozawa Ryuichi;Matsuda Noriyuki;Tanaka Keiji;Suzuki Tadashi
编码胞质去n -糖基化酶的人类肽：n -糖基化酶基因（NGLY1）的突变导致先天性常染色体隐性遗传病。在啮齿类动物中，ngly1的缺失会导致严重的发育迟缓或死亡，但其潜在机制尚不清楚。在这项研究中，我们发现，编码识别糖蛋白的泛素连接酶亚基的ofFbxo6（也称为asFbs2）的缺失挽救了gly1- ko小鼠的致命相关缺陷。在InNGLY1-KO细胞中，FBS2过表达导致蛋白酶体活性明显抑制，引起细胞毒性。核因子，红细胞2样1 (NFE2L1，也称为NRF1)，一种内质网相关的转录因子，参与蛋白酶体亚基的表达，也被SCFFBS2inNGLY1-KO细胞异常泛素化，导致其滞留在细胞质中。然而，FBS2引起的细胞毒性可以通过过度表达“无聚糖”NRF1突变体而不考虑其转录活性，或者通过删除nrf1inngly1 - ko细胞来恢复。我们得出结论，由n -糖蛋白（主要是NRF1）的积累引起的蛋白酶体功能障碍是由scffbs2泛素化导致的NGLY1缺乏的发病机制。
Mutations in the human peptide:N-glycanase gene (NGLY1), which encodes a cytosolic de–N-glycosylating enzyme, cause a congenital autosomal recessive disorder. In rodents, the loss ofNgly1results in severe developmental delay or lethality, but the underlying mechanism remains unknown. In this study, we found that deletion ofFbxo6(also known asFbs2), which encodes a ubiquitin ligase subunit that recognizes glycoproteins, rescued the lethality-related defects inNgly1-KO mice. InNGLY1-KO cells, FBS2 overexpression resulted in the substantial inhibition of proteasome activity, causing cytotoxicity. Nuclear factor, erythroid 2–like 1 (NFE2L1, also known as NRF1), an endoplasmic reticulum–associated transcriptional factor involved in expression of proteasome subunits, was also abnormally ubiquitinated by SCFFBS2inNGLY1-KO cells, resulting in its retention in the cytosol. However, the cytotoxicity caused by FBS2 was restored by the overexpression of “glycan-less” NRF1 mutants, regardless of their transcriptional activity, or by the deletion ofNRF1inNGLY1-KO cells. We conclude that the proteasome dysfunction caused by the accumulation ofN-glycoproteins, primarily NRF1, ubiquitinated by SCFFBS2accounts for the pathogenesis resulting from NGLY1 deficiency.