ALS-associated exitron splicing produces UBQLN2 isoforms with distinct properties
Koo, A. S. H.; Zhou, J.; Mendez-Albelo, N. M.; Wei, Y.; Xu, W.; Zhao, X.; Dewey, C. N.; Tibbetts, R. S.
Show abstract
X-linked amyotrophic lateral sclerosis (ALS) implicated Ubiquilin 2 (UBQLN2) is expressed from a single exon. Here, we show that human UBQLN2 mRNA is alternatively spliced by virtue of a cryptic exonic intron (exitron) spanning the 5' untranslated region and the 5' end of UBQLN2 coding sequence. Splice-out of this exitron generates a spliced UBQLN2 (UBQLN2-Sp) transcript that is translated from codon M243 to produce an N-terminally truncated UBQLN2 isoform (UBQLN2-M243) with reduced stability, diminished proteasome targeting, and altered aggregation behavior following the introduction of ALS mutations. The RNA-binding proteins SRSF1 and PTBP1 control UBQLN2 splicing through binding to splice donor-proximal motifs, while TDP-43 was implicated as an indirect splicing repressor. UBQLN2 splicing was elevated and inversely correlated with UBQLN2 gene expression in the medial motor cortex of male ALS patients. These findings suggest that alternative splicing regulates UBQLN2 gene dosage and function, which may impact UBQLN2-ALS proteinopathy.
Matching journals
The top 11 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Formation of tRNA wobble inosine in humans is perturbed by a millennia-old mutation linked to intellectual disability 91%
- DEAD-box protein family member DDX28 is a negative regulator of HIF-2α and eIF4E2-directed hypoxic translation 91%
- Calcineurin broadly regulates the initiation of skeletal muscle-specific gene expression by binding target promoters and facilitating the interaction of the SWI/SNF chromatin remodeling enzyme 89%
Similar papers in this journal
Similar papers in this journal
- Global proteomics of Ubqln2-based murine models of ALS 93%
- Biochemical characterizations of Pontocerebellar Hypoplasia linked mutations of Target of Egr1 (TOE1) reveal impacts on thermal stability, ribonuclease activity, and oligomerization 90%
- Tau regulates Arc stability in neuronal dendrites via a proteasome-sensitive but ubiquitin-independent pathway 90%
Similar papers in this journal
- FUS modulates the level of ribosomal RNA modifications by regulating a subset of snoRNA expression 91%
- Genetic dissection of Down syndrome-associated alterations in APP/amyloid-β biology using mouse models 91%
- Tagging allows faithful tracing of expression and enhances biochemical detection of Ran Binding Protein 9 in vivo and reveals its interaction with Nucleolin. 91%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.