Spsb1-KO Mouse

Spsb1, or SPRY domain-containing and SOCS-box protein 1, is an E3 ligase adaptor protein. It is involved in multiple cellular processes and signaling pathways. Spsb1 can interact with various proteins to regulate their stability and function, thereby influencing pathways like the TGF-β signaling pathway, NF-κB activation, and others, which are crucial for processes such as myogenesis, cell survival, and innate immune responses [1,3,8]. Genetic models, especially knockout (KO) mouse models, have been valuable in studying its functions.

In septic mice, increased Spsb1 expression in skeletal muscle was observed. Spsb1 binds to TGF-β receptor-II (TβRII), leading to TβRII ubiquitination and destabilization, which impairs TβRII-Akt-Myogenin signaling, protein synthesis, myoblast fusion, and myogenic differentiation. Down-regulation of Spsb1 by AAV9-mediated shRNA in septic mice attenuated muscle weight loss and atrophy gene expression, indicating its role in sepsis-induced muscle atrophy [1]. In ovarian cancer cells, Spsb1 knockdown decreased cell viability, migration, and elevated p21 levels, suggesting it promotes cell survival by destabilizing p21 [2]. Depletion of Spsb1 in cells resulted in increased NF-κB activation, and over-expression suppressed NF-κB activity, showing its role as a negative regulator of NF-κB activation [3]. In breast cancer, Spsb1 is up-regulated during recurrence, protecting cells from apoptosis and promoting recurrence by potentiating c-MET signaling [4]. Spsb1 and Spsb4 can interact with and facilitate RevErbα ubiquitination and degradation, regulating circadian clock periodicity [5]. In EGF signaling, EGF up-regulates Spsb1, which ubiquitylates hnRNP A1, affecting alternative splicing and cell migration [7]. Spsb1 negatively regulates the TGF-β signaling pathway by enhancing TβRII ubiquitination and degradation [8]. In macrophages, Spsb1 controls the induction of inducible nitric oxide synthase (iNOS) and subsequent NO production downstream of TLR3 and TLR4 [9]. However, Spsb1 deficiency in mice did not affect spermatogenesis or male fertility [6].

In conclusion, Spsb1 plays diverse and essential roles in various biological processes. Its functions range from regulating myogenesis during inflammation, influencing cell survival in cancer, modulating NF-κB activation in innate immunity, to regulating circadian rhythms, alternative splicing, and immune responses. The use of Spsb1 KO mouse models has been instrumental in revealing its role in diseases such as sepsis-induced muscle atrophy and breast cancer recurrence, providing insights into potential therapeutic targets for these conditions.

References:

1. Li, Yi, Dörmann, Niklas, Brinschwitz, Björn, Müller, Oliver J, Fielitz, Jens. 2023. SPSB1-mediated inhibition of TGF-β receptor-II impairs myogenesis in inflammation. In Journal of cachexia, sarcopenia and muscle, 14, 1721-1736. doi:10.1002/jcsm.13252. https://pubmed.ncbi.nlm.nih.gov/37209006/

2. Kim, Hyun-Jung, Kim, Hye Jin, Kim, Mi-Kyung, Kim, Seung Cheol, Ju, Woong. 2019. SPSB1 enhances ovarian cancer cell survival by destabilizing p21. In Biochemical and biophysical research communications, 510, 364-369. doi:10.1016/j.bbrc.2019.01.088. https://pubmed.ncbi.nlm.nih.gov/30712944/

3. Georgana, Iliana, Maluquer de Motes, Carlos. 2020. Cullin-5 Adaptor SPSB1 Controls NF-κB Activation Downstream of Multiple Signaling Pathways. In Frontiers in immunology, 10, 3121. doi:10.3389/fimmu.2019.03121. https://pubmed.ncbi.nlm.nih.gov/32038638/

4. Feng, Yi, Pan, Tien-Chi, Pant, Dhruv K, Ruth, Jason R, Chodosh, Lewis A. 2014. SPSB1 promotes breast cancer recurrence by potentiating c-MET signaling. In Cancer discovery, 4, 790-803. doi:10.1158/2159-8290.CD-13-0548. https://pubmed.ncbi.nlm.nih.gov/24786206/

5. Mekbib, Tsedey, Suen, Ting-Chung, Rollins-Hairston, Aisha, DeBruyne, Jason P. 2019. The E3 Ligases Spsb1 and Spsb4 Regulate RevErbα Degradation and Circadian Period. In Journal of biological rhythms, 34, 610-621. doi:10.1177/0748730419878036. https://pubmed.ncbi.nlm.nih.gov/31607207/

6. Hu, Haoyue, Zhu, Yue, Jiang, Bing, Wu, Yibo, Xi, Xiaoxue. 2025. Testis-enriched Spsb1 is not required for spermatogenesis and fertility in mice. In American journal of translational research, 17, 1824-1833. doi:10.62347/JFJX7128. https://pubmed.ncbi.nlm.nih.gov/40226024/

7. Wang, Feng, Fu, Xing, Chen, Peng, Hu, Ronggui, Hui, Jingyi. 2017. SPSB1-mediated HnRNP A1 ubiquitylation regulates alternative splicing and cell migration in EGF signaling. In Cell research, 27, 540-558. doi:10.1038/cr.2017.7. https://pubmed.ncbi.nlm.nih.gov/28084329/

8. Liu, Sheng, Nheu, Thao, Luwor, Rodney, Nicholson, Sandra E, Zhu, Hong-Jian. 2015. SPSB1, a Novel Negative Regulator of the Transforming Growth Factor-β Signaling Pathway Targeting the Type II Receptor. In The Journal of biological chemistry, 290, 17894-17908. doi:10.1074/jbc.M114.607184. https://pubmed.ncbi.nlm.nih.gov/26032413/

9. Lewis, Rowena S, Kolesnik, Tatiana B, Kuang, Zhihe, Norton, Raymond S, Nicholson, Sandra E. 2011. TLR regulation of SPSB1 controls inducible nitric oxide synthase induction. In Journal of immunology (Baltimore, Md. : 1950), 187, 3798-805. doi:10.4049/jimmunol.1002993. https://pubmed.ncbi.nlm.nih.gov/21876038/