USP15 Deubiquitinates TUT1 Associated with RNA Metabolism and Maintains Cerebellar Homeostasis

Abstract

Precise regulation of RNA metabolism is crucial for dynamic gene expression and controlling cellular functions. In the nervous system, defects in RNA metabolism are implicated in disturbing brain homeostasis and development. Here we report that deubiquitinating enzyme, ubiquitin specific peptidase 15 (USP15), deubiquitinates terminal uridylyl transferase 1 (TUT1) and changes global RNA metabolism. We found that the expression of USP15 redistributes TUT1 from nucleolus to nucleoplasm, resulting in the stabilization of U6-snRNA. We also found that lack of the Usp15 gene induces impairment in motor ability with the unconventional cerebellar formation. Moreover, inhibition of the USP15-TUT1 cascade triggered mild and chronic endoplasmic reticulum (ER) stress. Therefore, our results suggest that USP15 is crucial for mRNA metabolism and maintains a healthy brain. These findings provide a possibility that disturbance of the USP15-TUT1 cascade may induce chronic and mild ER stress, leading to an acceleration of neurodegenerative phenotype.

Autism-associated mutation in Hevin/Sparcl1 induces endoplasmic reticulum stress through structural instability

“…A defect in Usp15 increases the probability of splicing error and produces various abnormal variants. We also found that impaired USP15 induces the endoplasmic reticulum (ER) stress although the mechanism linking splicing error to ER stress has not been clarified 18 (Fig.1A). Because Usp15 gene is linked to ASD 2,19,20 , we looked for the ASD-associated abnormal variants, which have changed splicing upon Usp15 deficiency and are involved in the UPR pathway.…”

“…Previously, we reported that the deubiquitinating enzyme, USP15, deubiquitinates U6 snRNA-specific terminal uridylyl transferase 1 (TUT1) and regulates the spliceosome cascade 18 . A defect in Usp15 increases the probability of splicing error and produces various abnormal variants.…”

“…Because Usp15 gene is linked to ASD 2,19,20 , we looked for the ASD-associated abnormal variants, which have changed splicing upon Usp15 deficiency and are involved in the UPR pathway. To do this, we checked the dataset of microarray analysis from our previous study 18 and found that the 3’-region of hevin transcript tends to be lacking in Usp15 deficient brains (Fig.1B, Supplementary Table). Thus, we speculated that the 3’-region of hevin transcript is susceptible to abnormalities in the spliceosome cascade regulated by USP15.…”

USP15 in Cancer and Other Diseases: From Diverse Functionsto Therapeutic Targets

“…USP15 acts in certain diseases through the transcriptional regulation of target genes. USP15 deubiquitinates and redistributes terminal uridylyl transferase 1 (TUT1) from the nucleolus to the nucleoplasm, resulting in the stabilization of U6 snRNA, thereby regulating the neurodegenerative phenotype [ 105 ]. USP15 also deubiquitinates and opposes R-SMAD monoubiquitylation to prevent R-SMADs recognizing the promoters involved in the differentiation of mesenchymal stem cells from osteoblasts [ 106 ].…”

Acute Myeloid Leukemia-Related Proteins Modified by Ubiquitin and Ubiquitin-like Proteins

“…USP15 is a DUB that belongs to the USP family and is involved in numerous functions. USP15 deubiquitinates the Ub E3 ligase MDM2, eukaryotic initiation factor 4A-I (EIF4A1), terminal uridylyl transferase 1 (TUT1), and FK506-binding protein 5 (FKBP5) [ 109 , 110 , 111 , 112 , 113 ]. TRAF-interacting protein with a forkhead-associated domain B (TIFAB) has been implicated in various cellular signaling pathways associated with hematopoietic and immune cells [ 114 ].…”