Work

CUG repeat RNA-dependent proteasomal degradation of MBNL1 in a cellular model of myotonic dystrophy type 1

Year: 2024

Type: article

Abstract: Myotonic dystrophy type 1 (DM1) is caused by the expansion of a non-coding CTG repeat in DMPK . CUG-repeat-containing transcripts sequester the splicing regulator MBNL1 into nuclear RNA foci, causing aberrant splicing of many genes. Although the mislocalization of MBNL1 represents a causal event in DM1 pathogenesis, the effect of CUG repeat RNA on the protein level of MBNL1 remains unclear. Using a DM1 model cell line, we found that CUG repeat RNA caused a significant decrease in the protein, but not mRNA levels, of MBNL1. As CUG repeats did not decrease MBNL1 translation, we investigated protein degradation pathways. Although autophagy-related reagents induced little change, proteasome inhibitors partially recovered MBNL1 protein expression levels under conditions of CUG repeat expression and induced a slight, but significant, reversal of splicing dysregulation. MBNL1 was detected in the polyubiquitinated protein fraction, but MBNL1 polyubiquitination was not detected. Moreover, inhibition of the ubiquitin-activating enzyme E1 did not increase MBNL1 levels, suggesting that MBNL1 is a substrate of polyubiquitin-independent proteasomal degradation. These results suggest that CUG-repeat-induced proteasomal degradation partially contributes to the functional decline of MBNL1. • CUG repeat RNA causes a decrease in MBNL1 protein, besides its sequestration. • The downregulation of MBNL1 is mediated by proteasomal degradation. • Proteasome inhibition partially reversed the splicing dysregulation of MBNL1. • MBNL1 is suggested as a substrate of ubiquitin-independent proteasomal degradation.

Source: Biochemical and Biophysical Research Communications

DOI: 10.1016/j.bbrc.2024.150729

Authors: Yoshitaka Aoki, Motoaki Yanaizu, Ai Ohki, Kai Nishimiya, Yoshihiro Kino

Institution: Meiji Pharmaceutical University

Language: English

Topic: Genetic Neurodegenerative Diseases

Subfield: Cellular and Molecular Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $2,880