Sf3b3-KO Mouse

SF3B3, also known as splicing factor 3b subunit 3, is a component of U2 small nuclear ribonucleoproteins, which is crucial for the early stages of spliceosome assembly, playing a key role in pre-mRNA splicing [1,2,3]. It is involved in various biological pathways and has overall importance in maintaining normal cellular functions. Genetic models, such as gene-knockout (KO) or conditional-knockout (CKO) mouse models, can be valuable tools to study its functions.

In colorectal cancer (CRC), SF3B3 is upregulated and associated with poor survival. RNA silencing-mediated inhibition of SF3B3 suppresses CRC cell proliferation and metastasis both in vitro and in vivo. This is accompanied by mitochondria injury, increased reactive oxygen species (ROS), and apoptosis. Mechanistically, SF3B3 silencing increases mTOR exon-skipped splicing, suppressing lipogenesis via the mTOR-SREBF1-FASN signaling pathway [1].

In type 2 immunity, nuclear AGO3 interacts with SF3B3 to aid global mRNA splicing, especially of the Nisch gene, regulating the expansion of type 2 immunity in CD4+ T helper lymphocytes [2].

In ZIKV infection, SF3B3 overexpression inhibits ZIKV replication by promoting IFN-stimulated gene (ISG) expression, while its silencing promotes ZIKV replication by inhibiting ISG expression. SF3B3 also regulates GCH1 expression, and ZIKV NS5 binds to SF3B3 to modulate the host immune response against ZIKV replication [3].

In hyperuricemia-induced renal interstitial fibrosis, elevated SF3B3 is observed in renal tissues of HN rats. Suppressed HDAC3 relieves HN-induced RIF through restoring miR-19b-3p and knocking down SF3B3 [4].

In paraquat-induced neuronal damage, PQ exposure reduces SF3B3 protein expression in Neuro-2a cells, and knockdown of SF3B3 exacerbates PQ-induced cell viability decrease and TH protein expression reduction, while overexpressing SF3B3 reverses these effects [5].

In invasive breast carcinoma, SF3B3 is identified as a negative autophagic regulator, and siRNA/shRNA-SF3B3 can induce autophagy-associated cell death in vitro and in vivo breast cancer models [6].

In estrogen-receptor-positive breast cancer, SF3B3 expression levels are increased in endocrine-resistant cell lines and are significantly correlated with overall survival in ER-positive tumors [7].

In hepatocellular carcinoma, LINC01348 complexes with SF3B3 to modulate EZH2 pre-mRNA alternative splicing, affecting JNK/c-Jun activity and Snail expression, and SF3B3 promotes EZH2 exon14 inclusion in renal cancer, contributing to tumorigenesis [8,9].

In conclusion, SF3B3 is essential for pre-mRNA splicing and is involved in multiple biological processes and diseases. Studies using KO or CKO mouse models (or other loss-of-function experiments) have revealed its role in diseases such as cancer, viral infection, and fibrosis. These findings provide insights into the biological functions of SF3B3 and potential therapeutic targets for related diseases.

References:

1. Xu, Tong, Li, Xichuan, Zhao, Wennan, Zhang, Chunze, Zhang, Youcai. 2024. SF3B3-regulated mTOR alternative splicing promotes colorectal cancer progression and metastasis. In Journal of experimental & clinical cancer research : CR, 43, 126. doi:10.1186/s13046-024-03053-4. https://pubmed.ncbi.nlm.nih.gov/38671459/

2. Guidi, Riccardo, Wedeles, Christopher, Xu, Daqi, Hackney, Jason A, Wilson, Mark S. 2023. Argonaute3-SF3B3 complex controls pre-mRNA splicing to restrain type 2 immunity. In Cell reports, 42, 113515. doi:10.1016/j.celrep.2023.113515. https://pubmed.ncbi.nlm.nih.gov/38096048/

3. Chen, Tanxiu, Yang, Hao, Liu, Penghui, Lu, Shuaiyao, Peng, Xiaozhong. 2022. Splicing factor SF3B3, a NS5-binding protein, restricts ZIKV infection by targeting GCH1. In Virologica Sinica, 38, 222-232. doi:10.1016/j.virs.2022.12.005. https://pubmed.ncbi.nlm.nih.gov/36572150/

4. Hu, Langtao, Yang, Kai, Mai, Xing, Wei, Jiali, Ma, Chunyang. 2022. Depleted HDAC3 attenuates hyperuricemia-induced renal interstitial fibrosis via miR-19b-3p/SF3B3 axis. In Cell cycle (Georgetown, Tex.), 21, 450-461. doi:10.1080/15384101.2021.1989899. https://pubmed.ncbi.nlm.nih.gov/35025700/

5. Wang, Junxiang, Weng, Yali, Li, Yinhan, Wu, Siying, Li, Huangyuan. 2023. The interplay between lncRNA NR_030777 and SF3B3 in neuronal damage caused by paraquat. In Ecotoxicology and environmental safety, 255, 114804. doi:10.1016/j.ecoenv.2023.114804. https://pubmed.ncbi.nlm.nih.gov/36948007/

6. Zhang, Shouyue, Zhang, Jin, An, Yang, Xu, Heng, Liu, Bo. 2020. Multi-omics approaches identify SF3B3 and SIRT3 as candidate autophagic regulators and druggable targets in invasive breast carcinoma. In Acta pharmaceutica Sinica. B, 11, 1227-1245. doi:10.1016/j.apsb.2020.12.013. https://pubmed.ncbi.nlm.nih.gov/34094830/

7. Gökmen-Polar, Yesim, Neelamraju, Yaseswini, Goswami, Chirayu P, Janga, Sarath Chandra, Badve, Sunil. 2014. Expression levels of SF3B3 correlate with prognosis and endocrine resistance in estrogen receptor-positive breast cancer. In Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 28, 677-85. doi:10.1038/modpathol.2014.146. https://pubmed.ncbi.nlm.nih.gov/25431237/

8. Lin, Yang-Hsiang, Wu, Meng-Han, Liu, Yi-Chung, Yeh, Chau-Ting, Lin, Kwang-Huei. 2021. LINC01348 suppresses hepatocellular carcinoma metastasis through inhibition of SF3B3-mediated EZH2 pre-mRNA splicing. In Oncogene, 40, 4675-4685. doi:10.1038/s41388-021-01905-3. https://pubmed.ncbi.nlm.nih.gov/34140643/

9. Chen, Ke, Xiao, Haibing, Zeng, Jin, Xu, Hua, Ye, Zhangqun. 2016. Alternative Splicing of EZH2 pre-mRNA by SF3B3 Contributes to the Tumorigenic Potential of Renal Cancer. In Clinical cancer research : an official journal of the American Association for Cancer Research, 23, 3428-3441. doi:10.1158/1078-0432.CCR-16-2020. https://pubmed.ncbi.nlm.nih.gov/27879367/