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A critical step in preserving protein homeostasis is the recognition, binding, unfolding, and translocation of protein substrates by six AAA-ATPase proteasome subunits (ATPase-associated with various cellular activities) termed PSMC1-6, which are required for degradation of proteins by 26 S proteasomes. Here, we identified 15 de novo missense variants in the PSMC3 gene encoding the AAA-ATPase proteasome subunit PSMC3/Rpt5 in 23 unrelated heterozygous patients with an autosomal dominant form of neurodevelopmental delay and intellectual disability. Expression of PSMC3 variants in mouse neuronal cultures led to altered dendrite development, and deletion of the PSMC3 fly ortholog Rpt5 impaired reversal learning capabilities in fruit flies. Structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune programs. The proteostatic perturbations in T cells from patients with PSMC3 variants correlated with a dysregulation in type I interferon (IFN) signaling in these T cells, which could be blocked by inhibition of the intracellular stress sensor protein kinase R (PKR). These results suggest that proteotoxic stress activated PKR in patient-derived T cells, resulting in a type I IFN response. The potential relationship among proteosome dysfunction, type I IFN production, and neurodevelopment suggests new directions in our understanding of pathogenesis in some neurodevelopmental disorders.

Children with Down syndrome are at a high risk of developing transient abnormal myelopoiesis (TAM; synonym: TMD) or myeloid leukemia (ML-DS). While most patients with TAM are asymptomatic and go into spontaneous remission without a need for therapy, around 20% of patients die within the first six months due to TAM-related complications. Another 20-30% of patients progress from TAM to ML-DS. ML-DS patients are particularly vulnerable to therapy-associated toxicity, but the prognosis of relapsed ML-DS is extremely poor - thus, ML-DS therapy schemata must strive for a balance between appropriate efficacy (to avoid relapses) and treatment-related toxicity. This guideline presents diagnostic and therapeutic strategies for TAM and ML-DS based on the experience and results of previous clinical studies from the BFM working group, which have helped reduce the risk of early death in symptomatic TAM patients using low-dose cytarabine, and which have achieved excellent cure rates for ML-DS using intensity-reduced treatment protocols.Kinder mit Down-Syndrom haben ein hohes Risiko, eine transiente abnorme Myelopoese (TAM; Synonym: TMD) oder myeloische Leukämie (ML-DS) zu entwickeln. Während die meisten Patienten mit TAM asymptomatisch bleiben und ohne Therapie eine Spontanremission erreichen, sterben ca. 20% der Patienten innerhalb der ersten sechs Monate an TAM-bedingten Komplikationen. Weitere 20–30% der Patienten zeigen einen Progress von TAM zu ML-DS. Patienten mit ML-DS sind besonders durch therapieassoziierte Toxizität gefährdet. Gleichzeitig ist die Prognose nach einem Rückfall sehr schlecht. Daher muss die Therapieintensität so gewählt werden, dass einerseits Rückfälle verhindert und andererseits therapiebedingte Komplikationen minimiert werden. Diese Richtlinie präsentiert diagnostische und therapeutische Maßnahmen für Patienten mit TAM und ML-DS, die auf den Erfahrungen und Ergebnissen früherer klinischer Studien der BFM-Arbeitsgruppe basieren, welche dazu beigetragen haben, das frühe Mortalitätsrisiko von symptomatischen TAM Patienten unter Einsatz von niedrig dosiertem Cytarabin zu reduzieren und mit intensitätsreduzierten Chemotherapieprotokollen hervorragende Heilungsraten für ML-DS Patienten zu erzielen.

The supply of MHC class I-restricted peptides is primarily ensured by the degradation of intracellular proteins via the ubiquitin-proteasome system. Depending on the target and the enzymes involved, ubiquitination is a process that may dramatically vary in terms of linkages, length, and attachment sites. Here we identified the unique lysine residue at position 124 of the NY-ESO-1 cancer/testis antigen as the acceptor site for the formation of canonical Lys-48-linkages. Interestingly, a lysine-less form of NY-ESO-1 was as efficient as its wild-type counterpart in supplying the HLA-A*0201-restricted NY-ESO-1157–165 antigenic peptide. In fact, we show that the regulation of NY-ESO-1 processing by the ubiquitin receptors Rpn10 and Rpn13 as a well as by the standard and immunoproteasome is governed by non-canonical ubiquitination on non-lysine sites. In summary, our data underscore the significance of atypical ubiquitination in the modulation of MHC class I antigen processing.