Cytoplasmic Aggregates of Splicing Factor Proline‐Glutamine Rich Disrupt Nucleocytoplasmic Transport and Induce Persistent Stress Granules
Splicing factor proline-glutamine rich (SFPQ), a multifunctional RNA-binding protein (RBP), shows cytoplasmic colocalisation with stress granule (SG) markers; however, the causative relationship and mechanism underlying this coalescence of SFPQ aggregates and SGs remain unclear. In this study, we demonstrate that SFPQ lacking its nuclear localisation sequence spontaneously forms cytoplasmic aggregates that abnormally incorporate immature RNA and induce persistent SGs. mRNA profiling showed that SFPQ mislocalisation induced extensive changes in RNA processing, with a subset of alternatively spliced transcripts associated with nucleocytoplasmic transport. Notably, these altered transporters were sequestered into SFPQ aggregates, constituting aberrant protein-RNA complexes. Importantly, suppression of SG nucleation could not block cytoplasmic SFPQ aggregation with immature RNA and nucleocytoplasmic transporters, both of which, however, were moderately ameliorated by the inhibition of alternative splicing or nuclear export. Our results unveil the physiopathological role and mechanism for mislocalised SFPQ in the RNA metabolism, nucleocytoplasmic transport and pathological SGs.
Authors
- Zhenguo Chen (ORCID: https://orcid.org/0000-0003-3280-5201)
- Zicong Huang (ORCID: https://orcid.org/0000-0002-8088-3135)
- Yunhui Guo (ORCID: https://orcid.org/0000-0003-0182-9235)
- Chu‐Yu Huang (ORCID: https://orcid.org/0000-0002-6610-1360)
- Xiangjin Kang (ORCID: https://orcid.org/0000-0001-7377-7169)
- Qingqing Wu (ORCID: https://orcid.org/0000-0002-7475-5014)
- Ke Ma (ORCID: https://orcid.org/0000-0003-4942-9281)
- Yuge Zhuang (ORCID: https://orcid.org/0000-0002-6564-8989)
- Wei Huang (ORCID: https://orcid.org/0000-0003-3009-4741)
- Xiaoyuan Zhang (ORCID: https://orcid.org/0000-0001-5130-9495)
- Wenyuan Liu (ORCID: https://orcid.org/0000-0001-9681-0507)
- Xiaochun Bai (ORCID: https://orcid.org/0000-0001-9631-4781)
- Xiao Hu
- Hanbin Zhang (ORCID: https://orcid.org/0000-0002-0427-0070)
- Jinsheng Liu (ORCID: https://orcid.org/0000-0003-0759-2689)
- Runduan Yi
Institutions
- Jinan University (CN)
- Guangdong Province Stomatological Hospital (CN)
- Third Affiliated Hospital of Guangzhou Medical University (CN)
- Nanfang Hospital (CN)
- Guangdong Academy of Medical Sciences (CN)
- Guangdong Provincial People's Hospital (CN)
- Southern Medical University (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Journal of Cellular and Molecular Medicine
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1111/jcmm.70261
- Citations
- 2
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 0.47
Funders
- National Natural Science Foundation of China
- Basic and Applied Basic Research Foundation of Guangdong Province