Psmd11, the 26S proteasome non-ATPase regulatory subunit 11, is a key component of the 26S proteasome and the NRON complex. The 26S proteasome is crucial for maintaining cellular protein homeostasis by degrading ubiquitin-tagged proteins, and Psmd11 is involved in regulating proteasome activity. It also plays a role in the post-translational control of the molecular circadian clock, modulating the stability and nuclear translocation of circadian clock proteins like PER and CRY [2].

In functional studies, Psmd11 loss-of-function variants in 10 unrelated children led to early-onset syndromic intellectual disability, neurodevelopmental delay, and recurrent obesity. Drosophila melanogaster with depletion of the Psmd11 ortholog Rpn6 recapitulated the cognitive impairment, showing compromised reversal learning. In addition, Psmd11 loss of function caused impaired 26S proteasome assembly and an increased type I interferon gene signature mediated by PKR [1]. Conditional knockout mouse models (PSMD11flx/flx) were developed. Homozygous PSMD11 flx/flx mice had normal phenotypes, but constitutive single allele deletion led to growth retardation, and double allele knockout caused early embryonic lethality. Depletion of Psmd11 in mouse embryonic fibroblasts (MEFs) induced massive apoptosis, indicating its key role in early and postnatal mouse development [3].

In conclusion, Psmd11 is essential for normal development and cognitive function, as demonstrated by gene knockout studies in mice and Drosophila. Its role in proteasome assembly, interferon response, and circadian clock regulation provides insights into various biological processes and disease conditions such as neurodevelopmental disorders. The Psmd11 KO/CKO mouse models have been valuable in revealing its functions in development and disease-related mechanisms.

References:

1. Deb, Wallid, Rosenfelt, Cory, Vignard, Virginie, Küry, Sébastien, Ebstein, Frédéric. 2024. PSMD11 loss-of-function variants correlate with a neurobehavioral phenotype, obesity, and increased interferon response. In American journal of human genetics, 111, 1352-1369. doi:10.1016/j.ajhg.2024.05.016. https://pubmed.ncbi.nlm.nih.gov/38866022/

2. Cal-Kayitmazbatir, Sibel, Francey, Lauren J, Lee, Yool, Liu, Andrew C, Hogenesch, John B. 2023. PSMD11 modulates circadian clock function through PER and CRY nuclear translocation. In PloS one, 18, e0283463. doi:10.1371/journal.pone.0283463. https://pubmed.ncbi.nlm.nih.gov/36961772/

3. Zhao, Linlin, Zhao, Jinming, Zhang, Yingying, Wang, Chuanxin, Qi, Tonggang. 2021. Generation and identification of a conditional knockout allele for the PSMD11 gene in mice. In BMC developmental biology, 21, 4. doi:10.1186/s12861-020-00233-1. https://pubmed.ncbi.nlm.nih.gov/33517884/