PUBLICATION
Embryonic alcohol exposure disrupts the ubiquitin-proteasome system
- Authors
- Weeks, O., Miller, B.M., Pepe-Mooney, B.J., Oderberg, I.M., Freeburg, S.H., Smith, C.J., North, T.E., Goessling, W.
- ID
- ZDB-PUB-221209-7
- Date
- 2022
- Source
- JCI insight 7(23): (Journal)
- Registered Authors
- Goessling, Wolfram, North, Trista
- Keywords
- Cell stress, Development, Embryonic development, Molecular biology
- Datasets
- GEO:GSE172111
- MeSH Terms
-
- Ethanol/toxicity
- Zebrafish
- Ubiquitin*
- Proteasome Endopeptidase Complex*
- Animals
- PubMed
- 36477359 Full text @ JCI Insight
Citation
Weeks, O., Miller, B.M., Pepe-Mooney, B.J., Oderberg, I.M., Freeburg, S.H., Smith, C.J., North, T.E., Goessling, W. (2022) Embryonic alcohol exposure disrupts the ubiquitin-proteasome system. JCI insight. 7(23):.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping