Psmd11, the 26S proteasome non-ATPase regulatory subunit 11, is a component of the NRON complex and the lid of the 26S proteasome. It plays a key role in maintaining cellular protein homeostasis by participating in the ATP-dependent degradation of ubiquitinated proteins. It is also involved in pathways like the circadian clock regulation [2].

Pathogenic loss-of-function variants in Psmd11 in 10 unrelated children led to early-onset syndromic intellectual disability, neurodevelopmental delay, and recurrent obesity. In Drosophila, depletion of the Psmd11 ortholog Rpn6 recapitulated the cognitive impairment. Psmd11 loss-of-function also caused impaired 26S proteasome assembly and a persistent type I interferon gene signature [1]. In mice, homozygous Psmd11flx/flx mice were normal, while constitutive single allele deletion led to growth retardation, and double allele knockout caused early embryonic lethality. Conditional PSMD11 global knockout mice were developed, and depletion of Psmd11 induced massive apoptosis in mouse embryonic fibroblasts (MEFs) [3].

In summary, Psmd11 is crucial for normal development, as demonstrated by gene-knockout studies in mice. Its dysfunction is associated with neurodevelopmental disorders, obesity, and abnormal interferon responses, highlighting its significance in understanding the underlying mechanisms of these disease conditions.