文章基本信息

标题：Regulation of purine metabolism connects KCTD13 to a metabolic disorder with autistic features
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作者：Jon M. Madison ; Karen Duong ; Ellen F. Vieux 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：1
页码：1-33
DOI：10.1016/j.isci.2020.101935
语种：English
出版社：Elsevier
摘要：SummaryGenetic variation of the 16p11.2 deletion locus containing theKCTD13gene and ofCUL3is linked with autism. This genetic connection suggested that substrates of a CUL3-KCTD13 ubiquitin ligase may be involved in disease pathogenesis. Comparison ofKctd13mutant (Kctd13−/−) and wild-type neuronal ubiquitylomes identified adenylosuccinate synthetase (ADSS), an enzyme that catalyzes the first step in adenosine monophosphate (AMP) synthesis, as a KCTD13 ligase substrate. InKctd13−/−neurons, there were increased levels of succinyl-adenosine (S-Ado), a metabolite downstream of ADSS. Notably, S-Ado levels are elevated in adenylosuccinate lyase deficiency, a metabolic disorder with autism and epilepsy phenotypes. The increased S-Ado levels inKctd13−/−neurons were decreased by treatment with an ADSS inhibitor. Lastly, functional analysis of humanKCTD13variants suggests thatKCTD13variation may alter ubiquitination of ADSS. These data suggest that succinyl-AMP metabolites accumulate inKctd13−/−neurons, and this observation may have implications for our understanding of 16p11.2 deletion syndrome.Graphical abstractDisplay OmittedHighlights•KCTD13deletion leads to decreases in ubiquitination and increases in levels of ADSS•KCTD13deletion increases S-Ado levels, a metabolite observed in ADSL deficiency•Treatment ofKCTD13deletion neurons with an ADSS inhibitor reduces S-Ado levels•HumanKCTD13variants can alter ubiquitination of ADSSMolecular Neuroscience; Proteomics; Metabolomics