Embryonic alcohol exposure disrupts the ubiquitin-proteasome system.
Embryonic alcohol exposure disrupts the ubiquitin-proteasome system.
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DOI：
10.1172/jci.insight.156914
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发表时间：
2022-12-08
期刊：
影响因子：
8
通讯作者：
Goessling, Wolfram
中科院分区：
文献类型：
--
作者：
Weeks, Olivia;Miller, Bess M.;Pepe-Mooney, Brian J.;Oderberg, Isaac M.;Freeburg, Scott H.;Smith, Colton J.;North, Trista E.;Goessling, Wolfram
乙醇（EtOH）是一种常见的致畸剂，可破坏器官发育并导致胎儿酒精谱系障碍（FASD）;许多发育毒性机制尚不清楚。在这里，我们使用转录组学分析在一个既定的斑马鱼模型胚胎酒精暴露（EAE），以确定泛素-蛋白酶体系统（UPS）作为一个关键的目标乙醇在发展过程中。令人惊讶的是，EAE改变了20 S，19 S和11 S蛋白酶体基因的表达，并增加了泛素化蛋白的负荷。乙醇及其代谢产物乙醛以细胞类型特异性方式降低蛋白酶体肽酶活性。蛋白酶体20 S亚基β 1（psmb 1hi 2939 Tg）和蛋白酶体26 S亚基ATP酶6（psmc 6 hi 3593 Tg），遗传科斯定义了蛋白酶体功能降低对发育的影响。重要的是，psmb 1或psmc 6的缺失导致类似于EAE表型的广泛发育异常，包括生长受限、颅面结构异常、神经发育缺陷和肝胰腺成熟失败。此外，胰凝乳蛋白酶样蛋白酶体活性的药理学抑制增强了EAE对颅面结构、神经系统和内胚层的致畸作用。我们的研究确定了蛋白酶体作为EtOH暴露的靶点，并表明UPS中断有助于FASD的颅面、神经和内胚层表型。
Ethanol (EtOH) is a commonly encountered teratogen that can disrupt organ development and lead to fetal alcohol spectrum disorders (FASDs); many mechanisms of developmental toxicity are unknown. Here, we used transcriptomic analysis in an established zebrafish model of embryonic alcohol exposure (EAE) to identify the ubiquitin-proteasome system (UPS) as a critical target of EtOH during development. Surprisingly, EAE alters 20S, 19S, and 11S proteasome gene expression and increases ubiquitylated protein load. EtOH and its metabolite acetaldehyde decrease proteasomal peptidase activity in a cell type–specific manner. Proteasome 20S subunit β 1 (psmb1hi2939Tg) and proteasome 26S subunit, ATPase 6 (psmc6hi3593Tg), genetic KOs define the developmental impact of decreased proteasome function. Importantly, loss of psmb1 or psmc6 results in widespread developmental abnormalities resembling EAE phenotypes, including growth restriction, abnormal craniofacial structure, neurodevelopmental defects, and failed hepatopancreas maturation. Furthermore, pharmacologic inhibition of chymotrypsin-like proteasome activity potentiates the teratogenic effects of EAE on craniofacial structure, the nervous system, and the endoderm. Our studies identify the proteasome as a target of EtOH exposure and signify that UPS disruptions contribute to craniofacial, neurological, and endodermal phenotypes in FASDs.
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影响因子：
4.3
作者：
Eden E;Lipson D;Yogev S;Yakhini Z
通讯作者：
Yakhini Z
影响因子：
3.1
作者：
Angeles, Arkhjamil;Fung, Gabriel;Luo, Honglin
通讯作者：
Luo, Honglin
影响因子：
2.9
作者：
Bilotta, J;Barnett, JA;Saszik, S
通讯作者：
Saszik, S
影响因子：
3.9
作者：
DONOHUE, TM;TUMA, DJ;SORRELL, MF
通讯作者：
SORRELL, MF
DOI：
10.1155/2012/867141
发表时间：
2012
期刊：
International journal of proteomics
影响因子：
--
作者：
Mason S;Anthony B;Lai X;Ringham HN;Wang M;Witzmann FA;You JS;Zhou FC
通讯作者：
Zhou FC