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
