FMRP, FXR1 protein and Dlg4 mRNA, which are associated with fragile X syndrome, are involved in the ubiquitin–proteasome system

• Published in: Scientific reports Vol. 13; no. 1; p. 1956
• Main Authors: Shimizu, Hideo, Hohjoh, Hirohiko
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/337/474/2085; 631/337/474/582; 631/378/368; 692/617/375; Ataxia; Autophagy; Axonogenesis; Cell cycle; Disks Large Homolog 4 Protein - metabolism; Enzymes; FMR1 protein; Fragile X Mental Retardation Protein - genetics; Fragile X Mental Retardation Protein - metabolism; Fragile X syndrome; Fragile X Syndrome - genetics; Fragile X Syndrome - metabolism; FXR1 protein; Genes; Humanities and Social Sciences; Humans; Intellectual disabilities; mRNA; multidisciplinary; Pathogenesis; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein synthesis; Proteins; Proteolysis; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-Binding Proteins - genetics; Science; Science (multidisciplinary); Signal transduction; Ubiquitin; Ubiquitin - genetics; Ubiquitin - metabolism; Ubiquitination
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-29152-4

The ubiquitin–proteasome system (UPS) is a proteolytic pathway that is essential for life maintenance and vital functions, and its disruption causes serious impairments, e.g. , disease development. Thus, the UPS is properly regulated. Here we show novel UPS-related factors: the fragile X mental retardation 1 (FMR1) and Fmr1 autosomal homolog 1 (FXR1) proteins and discs large MAGUK scaffold protein 4 ( Dlg4 ) mRNA, which are associated with Fragile X syndrome, are involved in UPS activity. Fmr1 -, Fxr1 - and Dlg4 -knockdown and Fmr1 - and Fxr1 -knockdown resulted in increased ubiquitination and proteasome activity, respectively. FXR1 protein was further confirmed to be associated with proteasomes, and Dlg4 mRNA itself was found to be involved in the UPS. Knockdown of these genes also affected neurite outgrowth. These findings provide new insights into the regulatory mechanism of the UPS and into the interpretation of the pathogenesis of diseases in which these genes are involved as UPS-related factors.