A molecular brake that modulates spliceosome pausing at detained introns contributes to neurodegeneration

doi:10.1093/procel/pwac008

Protein Cell

2023, Vol. 14

Issue (5) : 318-336 https://doi.org/10.1093/procel/pwac008

RESEARCH ARTICLE

A molecular brake that modulates spliceosome pausing at detained introns contributes to neurodegeneration

Dawei Meng^1,^2,^3,⁴, Qian Zheng^1,^2,^3,⁴, Xue Zhang^1,^3,⁴, Xuejiao Piao^1,³, Li Luo⁵, Yichang Jia^1,^3,^4,⁵(

)

¹. Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China
². School of Life Sciences, Tsinghua University, Beijing 100084, China
³. School of Medicine, Tsinghua University, Beijing 100084, China
⁴. IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China
⁵. Tsinghua Laboratory of Brain and Intelligence, Tsinghua University, Beijing 100084, China

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Abstract

Emerging evidence suggests that intron-detaining transcripts (IDTs) are a nucleus-detained and polyadenylated mRNA pool for cell to quickly and effectively respond to environmental stimuli and stress. However, the underlying mechanisms of detained intron (DI) splicing are still largely unknown. Here, we suggest that post-transcriptional DI splicing is paused at the B^act state, an active spliceosome but not catalytically primed, which depends on Smad Nuclear Interacting Protein 1 (SNIP1) and RNPS1 (a serine-rich RNA binding protein) interaction. RNPS1 and B^act components preferentially dock at DIs and the RNPS1 docking is sufficient to trigger spliceosome pausing. Haploinsufficiency of Snip1 attenuates neurodegeneration and globally rescues IDT accumulation caused by a previously reported mutant U2 snRNA, a basal spliceosomal component. Snip1 conditional knockout in the cerebellum decreases DI splicing efficiency and causes neurodegeneration. Therefore, we suggest that SNIP1 and RNPS1 form a molecular brake to promote spliceosome pausing, and that its misregulation contributes to neurodegeneration.

Keywords SNIP1 RNPS1 spliceosome detained intron neurodegeneration

Corresponding Author(s): Yichang Jia

Issue Date: 29 May 2023

Cite this article:

Dawei Meng,Qian Zheng,Xue Zhang, et al. A molecular brake that modulates spliceosome pausing at detained introns contributes to neurodegeneration[J]. Protein Cell, 2023, 14(5): 318-336.

URL:

https://academic.hep.com.cn/pac/EN/10.1093/procel/pwac008
https://academic.hep.com.cn/pac/EN/Y2023/V14/I5/318

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